Microneedle injection and infusion apparatus and method of using same

ABSTRACT

A microneedle injection and infusion apparatus, and a method of using same. The apparatus can include a housing, a microneedle array holder for holding a microneedle array, and a shuttle that holds a cartridge (e.g., that contains an active agent). The microneedle array holder can be movable between a retracted position and an extended position. The shuttle can be movable between a first position in which the cartridge is not in fluid communication with a fluid path and a second position in which the cartridge is in fluid communication with the fluid path. The apparatus can further include an actuator movable between a first position and a second position. The method can include moving the actuator to its second position to allow the shuttle to move toward its second position, wherein movement of the shuttle toward its second position allows the microneedle array holder to move to its extended position.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/892,249, filed Nov. 19, 2015, which is a national stage filing under35 U.S.C. 371 of PCT/US2014/039133, filed May 22, 2014, which claims thebenefit of U.S. Provisional Patent Application No. 61/829,651, filed May31, 2013, the disclosure of which are incorporated by reference in theirentirety herein.

FIELD

The present disclosure generally relates to microneedle injection andinfusion devices for delivering an active agent to skin viamicroneedles.

BACKGROUND

Active agents (or drugs) are conventionally administered either orallyor by injection. Unfortunately, many agents can be ineffective or haveradically reduced efficacy when orally administered since they eitherare not absorbed or are adversely affected before entering thebloodstream and thus do not possess the desired activity. Further,orally administered agents may not take effect as quickly as injectedagents. On the other hand, the direct injection of the agent into thebloodstream, while assuring no modification of the agent duringadministration, is a difficult, inconvenient, painful and uncomfortableprocedure which sometimes results in poor patient compliance.

Transdermal delivery can provide a method of administering active agentsthat would otherwise need to be delivered via hypodermic injection orintravenous infusion. In addition, transdermal delivery, when comparedto oral delivery, avoids the harsh environment of the digestive tract,bypasses gastrointestinal drug metabolism, reduces first-pass effects,and avoids the possible deactivation by digestive and liver enzymes.

In some cases, however, the number of molecules that can be effectivelydelivered using transdermal delivery can be limited by the barrierproperties of skin. The main barrier to the transport of moleculesthrough the skin is the stratum corneum (the outermost layer of theskin).

A number of different skin treatment methods have been proposed in orderto increase the permeability or porosity of the outermost skin layers,such as the stratum corneum, thus enhancing drug delivery through orinto those layers. The stratum corneum is a complex structure of compactkeratinized cell remnants separated by lipid domains. The stratumcorneum is formed of keratinocytes, which make up the majority ofepidermal cells, that lose their nuclei and become corneocytes. Thesedead cells comprise the stratum corneum, which has a thickness of onlyabout 10-30 microns and protects the body from invasion by exogenoussubstances and the outward migration of endogenous fluids and dissolvedmolecules. Various skin treatment methods include the use ofmicroneedles, laser ablation, RF ablation, heat ablation, sonophoresis,iontophoresis, or a combination thereof.

Microneedle or micro-pin arrays, also sometimes referred to asmicrostructured transdermal systems (MTSs), provide intradermal deliveryof active agents, which otherwise would not penetrate the stratumcorneum. The sharp microneedle tip is designed to be able to penetratethe stratum corneum layer of the skin, but short enough not to puncturenerve endings, thus reducing or eliminating pain upon insertion.However, the penetration of microneedles to precise levels within theskin tissue and with good reproducibility is often a challenging task.Therefore, unlike the application of traditional patch-based deliverysystems, some existing MTSs require the assistance of external energy toensure efficient and reproducible penetration of microneedles intobiological tissue at desired depths. This assistance can be achieved byutilizing an apparatus device, which can either be used afterpositioning the microneedle array on the skin surface, or the apparatusdevice can be integrated with an array of microneedles and, uponactivation, can deliver the microneedle array into the skin. Themicroneedles help to create microchannels in the skin, which in someembodiments, can facilitate delivering an active ingredient. In someconstructions, active component(s) may be coated on the microneedlearray and delivered directly through the skin when the stratum corneumis punctured by the microneedles. One advantage of MTS systems overother skin treatment methods is a reduced-pain mode of delivery.

SUMMARY

Some embodiments of the present disclosure provide a microneedleinjection and infusion apparatus that can include a housing having abase and a cavity that extends through the base to define an opening inthe base, wherein the base of the housing is configured to be positionedtoward a skin surface. The apparatus can further include a microneedlearray holder configured to hold a microneedle array and located in thehousing, the microneedle array holder movable with respect to theopening in the base of the housing between (i) a retracted position inwhich the microneedle array is recessed within the housing such that themicroneedle array does not contact the skin surface when the apparatusis positioned on the skin surface and the microneedle array is coupledto the microneedle array holder, and (ii) an extended position in whichat least a portion of the microneedle array is positioned to contact theskin surface via the opening when the apparatus is positioned on theskin surface and the microneedle array is coupled to the microneedlearray holder. The apparatus can further include a shuttle configured tohold and carry a cartridge. The cartridge can define a reservoirconfigured to contain an active agent. The shuttle can be movablebetween a first position in which the reservoir of the cartridge is notin fluid communication with a fluid path and a second position in whichthe reservoir is in fluid communication with the fluid path. Theapparatus can further include an actuator movable between a firstposition and a second position, wherein movement of the actuator to thesecond position releases the shuttle from its first position and allowsthe shuttle to move toward its second position, and wherein movement ofthe shuttle toward its second position releases the microneedle arrayholder from the retracted position and allows the microneedle arrayholder to move to the extended position.

Some embodiments of the present disclosure provide a method of using amicroneedle injection apparatus. The method can include providing amicroneedle injection apparatus. The apparatus can include a housinghaving a base and a cavity that extends through the base to define anopening in the base, wherein the base of the housing is configured to bepositioned toward a skin surface. The apparatus can further include amicroneedle array holder configured to hold a microneedle array andlocated in the housing, the microneedle array holder movable withrespect to the opening in the base of the housing between (i) aretracted position in which the microneedle array is recessed within thehousing such that the microneedle array does not contact the skinsurface when the apparatus is positioned on the skin surface and themicroneedle array is coupled to the microneedle array holder, and (ii)an extended position in which at least a portion of the microneedlearray is positioned to contact the skin surface via the opening when theapparatus is positioned on the skin surface and the microneedle array iscoupled to the microneedle array holder. The apparatus can furtherinclude a shuttle configured to hold and carry a cartridge. Thecartridge can define a reservoir configured to contain an active agent.The shuttle can be movable between a first position in which thereservoir is not in fluid communication with a fluid path and a secondposition in which the reservoir is in fluid communication with the fluidpath. The apparatus can further include an actuator movable between afirst position and a second position. The method can further includemoving the actuator to its second position to allow the shuttle to movetoward its second position, wherein movement of the shuttle toward itssecond position allows the microneedle array holder to move to itsextended position.

Other features and aspects of the present disclosure will becomeapparent by consideration of the detailed description and accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a front assembled top perspective view of a microneedleinjection and infusion apparatus according to one embodiment of thepresent disclosure, the apparatus including a cover, and injectionassembly, and an infusion assembly.

FIG. 2 is a side view of the apparatus of FIG. 1.

FIG. 3 is a side cross-sectional view of the apparatus of FIGS. 1 and 2.

FIG. 4 is a front, top, partially exploded perspective view of theapparatus of FIGS. 1-3.

FIG. 5 is a front, bottom, partially exploded perspective view of theapparatus of FIGS. 1-4.

FIG. 6 is a front, top, exploded perspective view of the apparatus ofFIGS. 1-5.

FIG. 7 is a side cross-sectional view of the apparatus of FIGS. 1-6, theapparatus shown in a first condition with the cover removed.

FIG. 8 is a close-up, rear, top, partial perspective view of theapparatus of FIGS. 1-7, the apparatus shown in the first condition withthe cover removed.

FIG. 9 is a side cross-sectional view of the apparatus of FIGS. 1-8, theapparatus shown in a second condition.

FIG. 10 is a close-up, rear, top, partial perspective view of theapparatus of FIGS. 1-9, the apparatus shown in the second condition.

FIG. 11 is a side cross-sectional view of the apparatus of FIGS. 1-10,the apparatus shown in a third condition.

FIG. 12 is a close-up, rear, top, partial perspective view of theapparatus of FIGS. 1-11, the apparatus shown in the third condition.

FIG. 13 is a side cross-sectional view of the apparatus of FIGS. 1-12,the apparatus shown in a fourth condition.

FIG. 14 is a close-up front cross-sectional view of the apparatus ofFIGS. 1-13, the apparatus shown in the fourth condition.

FIG. 15 is a close-up front cross-sectional view of the apparatus ofFIGS. 1-14, the apparatus shown in a fifth condition.

FIG. 16 is a side cross-sectional view of the apparatus of FIGS. 1-15,the apparatus shown in the fifth condition.

FIG. 17 is a side cross-sectional view of the apparatus of FIGS. 1-16,the apparatus shown in a sixth condition.

FIG. 18 is a top plan view of the apparatus of FIGS. 1-17, the apparatusshown in the sixth condition.

FIG. 19 is a close-up side cross-sectional view of the apparatus shownin FIG. 9, taken of the portion enclosed in the circle labeled “19” inFIG. 9.

FIG. 20 is a close-up side cross-sectional view of the apparatus shownin FIG. 11, taken of the portion enclosed in the circle labeled “20” inFIG. 11.

FIG. 21 is a close-up side cross-sectional view of the apparatus shownin FIG. 17, taken of the portion enclosed in the circle labeled “21” inFIG. 17.

FIG. 22 is a side cross-sectional view of the apparatus of FIGS. 1-21,the apparatus shown in a seventh condition.

FIG. 23 is a top plan view of the apparatus of FIGS. 1-20, the apparatusshown in the seventh condition.

FIG. 24 is a top perspective view of the cover of FIGS. 1-6.

FIG. 25 is a bottom perspective view of the cover of FIGS. 1-6 and 24.

FIG. 26 is a top cross-sectional view of a portion of an infusionassembly according to another embodiment of the present disclosure.

FIG. 27 is a close-up side cross-sectional view of an exemplarymicroneedle array that can be employed with the apparatus of FIGS. 1-25,the microneedle array shown with the microneedles pointing upwardly.

DETAILED DESCRIPTION

Before any embodiments of the present disclosure are explained indetail, it is to be understood that the invention is not limited in itsapplication to the details of construction and the arrangement ofcomponents set forth in the following description or illustrated in thefollowing drawings. The invention is capable of other embodiments and ofbeing practiced or of being carried out in various ways. Also, it is tobe understood that the phraseology and terminology used herein is forthe purpose of description and should not be regarded as limiting. Theuse of “including,” “comprising,” or “having” and variations thereofherein is meant to encompass the items listed thereafter and equivalentsthereof as well as additional items. Unless specified or limitedotherwise, the terms “mounted,” “supported,” and “coupled,” andvariations thereof, are used broadly and encompass both direct andindirect mountings, supports, and couplings. It is to be understood thatother embodiments may be utilized, and structural or logical changes maybe made without departing from the scope of the present disclosure.Furthermore, terms such as “front,” “rear,” “top,” “bottom,” and thelike are only used to describe elements as they relate to one another,but are in no way meant to recite specific orientations of theapparatus, to indicate or imply necessary or required orientations ofthe apparatus, or to specify how the invention described herein will beused, mounted, displayed, or positioned in use.

The present disclosure generally relates to microneedle injection andinfusion apparatuses and methods of using same. Apparatuses of thepresent disclosure can include an array of microneedles that can beapplied to skin (or a biological membrane) to treat the skin (i.e.,create small holes or perforations or micropores in the skin) and canalso deliver an active agent to the skin. Apparatuses of the presentdisclosure can be configured to be activated by a single actuation toautomatically and reliably penetrate (or inject) a patient's skin with amicroneedle array (e.g., a hollow microneedle array) and thenautomatically release and dispense thereto a stored fluid (e.g., anactive agent) from a reservoir (e.g., a ready-to-use drug cartridge) ina controlled manner from an on-board infusion device into the skin viathe microneedles. That is, one user-actuated action can initiate bothinjection and infusion without requiring the user to perform anyadditional steps after the single initial actuation.

The phrase “hollow microneedle” refers to a specific microscopicstructure that includes a lumen formed therein. The hollow microneedlesof the present disclosure are designed for piercing the stratum corneumto facilitate the delivery of active agents through the skin, e.g., viaeach lumen. By way of example, microneedles can include needle orneedle-like structures, as well as other structures capable of piercingthe stratum corneum and delivering the active agent. Additional detailsabout microneedles that can be employed with the apparatuses of thepresent disclosure are described in greater detail below.

Apparatuses of the present disclosure can be configured to appropriatelytime and stage a sequence of events following actuation, such that,e.g., the microneedles are in place, penetrating the skin, before theactive agent begins to be dispensed or released from the on-boardinfusion device. For example, in some embodiments, apparatuses of thepresent disclosure can include an injection assembly or device thatincludes a microneedle array holder, and an infusion assembly or devicethat includes a cartridge that defines a reservoir configured to containan active agent. An actuator can be actuated to cause the injectiondevice to inject microneedles into the skin and to initiate infusion ofthe active agent from the injection device through the injection deviceinto the skin. In some embodiments, at least a portion of the infusiondevice can hold the injection device in a retracted position until theactuator causes the infusion device to move and release the injectiondevice. By way of example only, and as described in greater detailbelow, the actuator can be moved from a first position to a secondposition, which releases a shuttle of the infusion device that holds andcarries the cartridge, which in turn releases at least a portion of theinjection device (e.g., the microneedle array holder). In someembodiments, the shuttle can continue moving after the injection devicepenetrates the skin to move the cartridge to an infusing position wherethe reservoir of the cartridge is in fluid communication with a fluidpath (e.g., including hollow microneedles penetrating the skin). Theactive agent can then be forced out of the reservoir of the cartridgeinto the fluid path to deliver the active agent to the skin.

In discussing the apparatuses of the present disclosure, the term“downward,” and variations thereof, is sometimes used to describe thedirection in which microneedles are pressed into skin, and “upward” todescribe the opposite direction. However, those of skill in the art willunderstand that the apparatuses can be used where the microneedles arepressed into skin at an angle to the direction of the earth's gravity,or even in a direction contrary to that of the earth's gravity, andthese terms are only used for simplicity and clarity to describerelative directions.

FIGS. 1-25 illustrate a microneedle injection and infusion apparatus 100according to one embodiment of the present disclosure. As shown, theapparatus 100 can include an injection assembly (or device) 101 and aninfusion assembly (or device) 103, which can be an on-board infusiondevice.

The phrase “on-board infusion device” generally refers to an assembly ordevice capable of delivering an active agent to the microneedles of theinjection assembly 101 for delivery to a patient's skin that forms aportion of, or is coupled to, and is operable with the injectionassembly 101.

In some embodiments, the apparatus 100 can be referred to as a“controlled fluid release apparatus.” In addition, the injectionassembly 101 can also be referred to as an “applicator” or a“microneedle applicator;” and the infusion assembly 103 can also bereferred to as a “fluid storage and delivery system or assembly.”

The apparatus 100 can further include a housing 102; an actuator 104; amicroneedle array holder 106 configured to hold and carry a microneedlearray 107 comprising a plurality of hollow microneedles 108; a cartridge110 defining a reservoir 111 configured to contain an active agent; anda cover 113. As shown in FIGS. 1, 2, 4 and 5, in some embodiments, thehousing 102 can include a ridged or texturized surface or portion 117 tofacilitate manually grasping and/or manipulating the apparatus 100.

In some embodiments, the cartridge 110 can be installed bymanufacturers, assemblers, or users. In addition, the cartridge 110 andthe microneedle array 107 can be replaced, thereby permitting reuse ofthe apparatus 100. Replaceable cartridges may provide an advantage ofbeing able to be cleaned, sterilized, filled, and refilled as comparedto microneedle devices having fixed or dedicated cartridges that areintegrally formed therewith.

As shown in FIG. 3, the injection assembly 101 can include themicroneedle array holder 106 and a microneedle array 107 (i.e., whencoupled to the microneedle array holder 106), and the infusion assembly103 can include the cartridge 110. In some embodiments, the apparatus100 can further include a fluid path 123 that is in fluid communicationwith or includes the microneedle array 107 (e.g., any surfaces ormanifolds thereof, as well as the hollow microneedles 108), when themicroneedle array 107 is coupled to the microneedle array holder 106. Asa result, the fluid path 123 can deliver an active agent to and throughthe hollow microneedles 108. Such a fluid path 123 can provide fluidcommunication between the injection assembly 101 and the infusionassembly 103 and therefore, in some embodiments, can be described asforming a portion of either assembly, or as a connection between theassemblies.

In some embodiments, at least a portion of the fluid path 123 can beformed by a conduit or channel positioned to fluidly connect thecartridge 110 and the microneedles 108. In some embodiments, thatconduit or channel can be provided by flexible tubing 129 (see FIGS. 3,4 and 6). In some embodiments, one end of such tubing can be coupled tothe microneedle array 107 and can travel with the microneedle array 107(and microneedle array holder 106). Such flexible tubing 129 can allow apiercing element 175 that is in fluid communication with the fluid path123 and is configured to pierce or puncture the cartridge 110 to remainin a fixed location within the housing 102. As such, the piercingelement 175 need not travel with the microneedle array 107 and holder106. Such tubing 129 can be formed of a variety of materials, including,but not limited to, polymeric materials, such as polypropylene,polyethylene, silicone, other suitable polymeric materials, or acombination thereof. However, in some embodiments, the piercing element175 can be fixedly coupled to the holder 106, the apparatus 100 need notinclude the flexible tubing 129, and the piercing element 175 can bemovable in the housing 102 with the microneedle array 107 and the holder106.

The infusion assembly 103 can further include a shuttle 125 configuredto hold and carry the cartridge 110 into fluid communication with thefluid path 123. The actuator 104 can be operable to actuate injection,movement of the shuttle 125 (and, accordingly, the cartridge 110), andinfusion of the active agent into the fluid path 123 and out the hollowmicroneedles 108.

In some embodiments, the microneedles 108 can be configured to treatskin (i.e., create small holes or perforations or micropores in theskin) and deliver an active agent via skin, particularly, mammalianskin, and particularly, transdermally. Various microneedles that can beemployed in apparatuses and methods of the present disclosure aredescribed in greater detail below. Each hollow microneedle 108 includesa lumen 127 (see FIGS. 14 and 15). While a “plurality of microneedles”108 is described in the present disclosure, it should be understood thatnot all of the microneedles 108 in a given array 107 are required topenetrate the skin (or to be coated with an active agent in embodimentsin which the microneedles 108 include a coating) in a given use.

The term “transdermally,” and variations thereof, is generally used torefer to any type of delivery of an active ingredient that crosses anyportion of skin. That is, transdermally can generally include systemicdelivery (i.e., where the active ingredient is transported across, orsubstantially through, the dermis such that the active ingredient isdelivered into the bloodstream), as well as intradermal delivery (i.e.,where the active ingredient is transported partially through the dermis,e.g., across the outer layer (stratum corneum) of the skin, where theactive ingredient is delivered into the skin, e.g., for treatingpsoriasis or for local anesthetic delivery). That is, transdermaldelivery as used herein includes delivery of an active ingredient thatis transported across or through at least a portion of skin (but notnecessarily all of the layers of skin), rather than merely beingtopically applied to an outer layer of the skin.

In some embodiments, the housing 102 can be self-contained and compactlyconstructed to provide a relatively low profile and small footprint for,among other factors, ease of use and patient comfort. The term“footprint” generally refers to the surface area occupied by an item(e.g., the apparatus 100), e.g., on a skin surface. The footprint of agiven item can be thought of as the area taken up by an outline of theoutermost dimensions of the item. In some embodiments, “low profile” canrefer to an apparatus 100 that is generally wide in relation to itsheight. That is, a “low profile” device can be one that has a dimensionthat extends along the skin surface that is greater than a dimensionwhich extends generally normal to (and away from) the skin surface. Saidanother way, “low profile” can refer to a device having a skin-paralleldimension that is greater than its skin-normal dimension.

As shown, the apparatus 100, and the housing 102, can be elongated alonga longitudinal axis L (see, e.g., FIGS. 1 and 2) and can be configuredto be oriented substantially parallel with respect to a skin surfacewhen in use. Such a configuration can provide a low profile for theapparatus 100. A low profile can reduce the likelihood of themicroneedles 108 becoming dislodged during penetration and/or infusionand can facilitate hands-free wear. While designing the apparatus 100such that the longitudinal axis L will be oriented generally parallel toa patient's skin surface during use can provide a low-profile andcompact design, other orientations can be employed.

In some embodiments, the housing 102 can be formed of more than oneportion. In some embodiments, the housing 102 can include a first (orupper) portion 120 adapted to be coupled (e.g., removably orpermanently) to a second (or lower) portion 122, such that the firstportion 120 can function as a cover for the second portion 122. At leasta portion of the housing 102 (e.g., the first portion 120) can includeone or more light-transmissive windows 124, which in some embodiments,can allow a user to observe the progress of at least a portion of theinfusion process. For example, as shown in FIGS. 18 and 23 and describedin greater detail below, in some embodiments, the infusion assembly 103can include one or more indicators 126 for indicating the progress ofinfusion, and such indicators 126 can be visible via the window 124. Thewindow(s) 124 need not be entirely transparent but at least partiallytransmissive to wavelengths in the visible spectrum (i.e., about 400 nmto about 700 nm) to allow for visual detection of the indicator(s) 126via the window(s) 124.

The second portion 122 of the housing 102 can be configured to hold andretain the injection assembly 101 and the infusion assembly 103. Each ofthe first portion 120 and the second portion 122 of the housing caninclude one or more retaining walls 105. The first portion 120 and thesecond portion 122 of the housing 102 can be configured to be coupledtogether by a variety of coupling means, including, but not limited to,press-fit engagement (also sometimes referred to as “friction-fitengagement” or “interference-fit engagement”), snap-fit engagement,magnets, hook-and-loop fasteners, adhesives, cohesives, clamps,stitches, staples, screws, nails, rivets, brads, crimps, detents,welding (e.g., sonic (e.g., ultrasonic) welding), any thermal bondingtechnique (e.g., heat and/or pressure applied to one or both of thecomponents to be coupled), other suitable coupling means, orcombinations thereof. By way of example only, in the embodiment of FIGS.1-25, the first portion 120 and the second portion 122 are configured tobe ultrasonically welded together. In addition, the housing 102 is shownas being split along its length into the first portion 120 and thesecond portion 122; however, other configurations are possible that alsofacilitate assembly and/or use of the apparatus 100.

In some embodiments, the housing 102 (e.g., the second portion 122 ofthe housing 102) can include a base 112 (see, e.g., FIGS. 3-5)configured to be positioned toward a skin surface 50 (see, e.g., FIG.7). The base 112 may be configured to touch the skin surface 50 duringinjection and/or infusion and may include a skin-contact adhesive.However, the base 112 of the embodiment illustrated in FIGS. 1-25 doesnot include an adhesive and is a non-adhesive surface. The base 112 ofthe housing 102 can extend along the entire length of the housing 102,but the base 112 of the housing 102 referenced herein is particularlyreferring to the base 112, or portion thereof, that is located adjacentthe injection assembly 101 and the actuator 104 that projects outwardlywith respect to the base 112, as described in greater detail below.Particularly, the base 112 of the housing 102 referenced herein isgenerally provided by or defined by a protrusion 119 that protrudes(e.g., downwardly) relative to the remainder of the housing 102 (seeFIGS. 4 and 5).

In the accompanying figures, it appears that a rear or tail end of theapparatus 100 (e.g., adjacent the infusion assembly 103 and oppositewhere the injection assembly 101 is located) is raised off of the skinsurface 50. While this may be the case, it is certainly possible thatthe tail end of the apparatus 100 would also rest against the skinsurface 50 in use. For example, the rear end of the apparatus 100 can beangled down toward the skin 50 to facilitate resting the rear end on theskin 50. In addition, in some embodiments, the base 112 of the housing102 in that region (or extending along the length of the apparatus 100)can further include a skin-contact adhesive and can be adhered to theskin. In addition, the protrusion 119 is shown by way of example only;however, it should be understood that the apparatus 100 can beconfigured not to include such a protrusion 119, and in someembodiments, the entire base 112 of the housing 102 can be flush withthe skin 50 or be configured to be adhered to the skin, e.g., afteractuation.

The housing 102 can further include or define a cavity (or chamber, orpocket, or recess, etc.) 114. As shown, the base 112 can define anopening 115 that opens into the cavity 114. Said another way, the cavity114 can extend through the base 112 to define the opening 115. Thehousing 102, and particularly, the cavity 114 (or a portion thereof) canbe configured to house at least a portion of the microneedle arrayholder 106 and the microneedle array 107 (e.g., when coupled to theholder 106), i.e., prior to application of the microneedles 108 to theskin 50.

The microneedle array holder 106 can be configured to be at leastpartially located in the cavity 114 of the housing 102 and can beconfigured to hold a microneedle array 107 within the cavity 114 of thehousing 102. The microneedle array holder 106 can also be movable withrespect to the housing 102 (i.e., with respect to the opening 115 in thehousing 102) to deliver the microneedles 108 to a substrate of interest(e.g., skin). As shown in FIG. 6, the microneedle array holder 106 caninclude a first (or bottom) side (or base) 121 that can be configured tobe positioned toward a skin surface, i.e., skin-facing, and which can beconfigured to receive the microneedle array 107. By way of example only,a microneedle array 107 can be coupled (e.g., removably coupled) to themicroneedle array holder 106 by a variety of coupling means, includingbut not limited to, press-fit engagement (also sometimes referred to as“friction-fit engagement” or “interference-fit engagement”), snap-fitengagement, magnets, hook-and-loop fasteners, adhesives, cohesives,clamps, stitches, staples, screws, nails, rivets, brads, crimps,detents, welding (e.g., sonic (e.g., ultrasonic) welding), any thermalbonding technique (e.g., heat and/or pressure applied to one or both ofthe components to be coupled), other suitable coupling means, orcombinations thereof.

The “microneedle array” 107 can include the microneedles 108 and anysupporting structure or substrate used to support the microneedles 108and/or to couple the microneedle array 107 to other structures orcomponents of the apparatus 100, such as the microneedle array holder106. For example, in some embodiments, the “microneedle array” 107 caninclude a substrate (or “carrier,” or “base”) 109 from which themicroneedles 108 protrude, as well as additional layers or carriers. Inthe embodiment illustrated in FIGS. 1-25, the microneedles 108 areintegrally formed with the substrate 109. However, it should beunderstood that additional layers can be employed in the microneedlearray 107, and other suitable configurations are possible. For example,in some embodiments, the microneedles 108 can be formed directly intothe substrate 109 which can then be coupled (e.g., mechanically andfluidly) to a base or additional layer.

In some embodiments, the apparatus 100 does not include the microneedlearray 107, but rather, the apparatus 100 can be configured to hold themicroneedle array 107 and to deliver the microneedle array 107 to theskin according to specified parameters, e.g., at a predetermined impactvelocity and/or force. Such specified parameters, for example, can beused to ensure delivery of the microneedles 108 to a predetermined depthof penetration.

The microneedle array 107 (e.g., the substrate 109) can include a firstside 116 comprising the microneedles 108 and a second side 118 oppositethe first side 116. The first side 116 can include a first major surface(e.g., defined by the substrate 109 in the illustrated embodiment) fromwhich the microneedles 108 protrude. The first side 116 can be orientedtoward the base 112 of the housing 102 (i.e., positioned to face theskin surface 50). That is, a microneedle array 107 can be coupled to themicroneedle array holder 106 such that the second side 118 faces themicroneedle array holder 106, and the first side 116 is oriented towardthe base 112 of the housing 102, i.e., positioned to face the skinsurface 50, or be “skin-facing.”

The housing 102, the actuator 104, the microneedle array holder 106and/or the microneedle array 107 (e.g., the substrate 109), the cover113, and the shuttle 125 can be formed of a variety of materials,including but not limited to, thermoset plastics (e.g., acetal resinavailable under the trade designation DELRIN® DuPont Corporation,Wilmington, Del.; other suitable thermoset plastics, or combinationsthereof), thermoplastics (e.g., polyethylene, polypropylene, othersuitable thermoplastics, or combinations thereof), or metals (e.g.,stainless steel, aluminum, other suitable metals, or combinationsthereof), or combinations thereof.

The actuator 104 can include an inner portion 130 configured to bereceived in (or extend into) the cavity 114 of the housing 102 and tointeract and/or engage with the injection assembly 101 and the infusionassembly 103. The actuator 104 can further include an outer portion 132coupled to the inner portion 130 and configured to extend out of thecavity 114 of the housing 102 and through the opening 115 of the housing102, such that the outer portion 132 can protrude outwardly of thehousing 102 and at least partially reside on the exterior of the housing102 to allow a user to manually manipulate and control the actuator 104.For example, as shown, in some embodiments, the outer portion 132 caninclude or function as a button or other manually engageable portion orelement. The outer portion 132 is illustrated by way of example as beinga push-button. By way of further example, the inner portion 130 and theouter portion 132 of the actuator 104 of FIGS. 1-25 are integrallyformed.

The actuator 104 can be movable with respect to the housing 102 (e.g.,with respect to the opening 115 in the base 112 of the housing 102) andthe microneedle array holder 106 between a first position P₁ (see FIGS.3-5, 7 and 8) and a second position P₂ (see FIGS. 9-13, 16-17 and 22) tocause the microneedle array holder 106 to move, respectively, between

-   -   (i) a first, retracted position H₁ (see, e.g., FIGS. 3, 4 and        7-12), in which the microneedle array 107 (when coupled to the        microneedle array holder 106) is recessed within the housing 102        (and/or the actuator 104, as described below), such that the        microneedle array 107 does not contact the skin 50 when the        apparatus 100 is positioned on the skin 50; and    -   (ii) a second, extended (or “impact” or “treatment”) position H₂        (see, e.g., FIGS. 15-17 and 22), in which at least a portion of        the microneedle array 107 (when coupled to the microneedle array        holder 106) is positioned to contact the skin 50 (e.g., via the        opening 115) when the apparatus is positioned on the skin 50.

In some embodiments, movement of the holder 106 from the retractedposition H₁ to the extended position H₂ can be dampened by one or moredampeners or shock-absorbing elements or materials, which is illustratedin FIGS. 13-15 and described below with respect to a dampener 163, asshown in FIGS. 6, 14 and 15.

As shown, in some embodiments, the actuator 104 can be movable from itsfirst position P₁ to its second position P₂ against the bias of abiasing element 128. As such, the actuator 104 can be biased in itsfirst position P₁ (e.g., downwardly) and can require a user to overcomethe bias of the biasing element 128 to actuate the apparatus 100. Thatis, the biasing force presented by the biasing element 128 representsthe force a user would need to overcome in order to actuate theapparatus 100. This biasing force can be controlled so as not to be toohigh or too low. If the biasing force is too low, the apparatus 100 maybe too sensitive and the apparatus 100 may be prematurely actuated,e.g., when a user merely intends to adhere the apparatus 100 to the skin50. However, if the biasing force is too high, the apparatus 100 may notbe able to be actuated by pressing it on soft skin. In some embodiments,the biasing force (e.g., provided by the biasing element 128), andtherefore, also the actuation force of the apparatus 100 can be at least5 N, in some embodiments, at least 6 N, and in some embodiments, is 8 N.In some embodiments, the biasing force (and hence, the actuation force)can be no greater than 15 N, in some embodiments, no greater than 12 N,and in some embodiments, no greater than 10 N.

As shown, the microneedle array holder 106 can be movable between theretracted position H₁ and the extended position H₂ independently of anyportion of the infusion assembly 103, such as the cartridge 110 and theshuttle 125, which can minimize the amount of structure that needs to bemoved to impact the skin 50 with the microneedles 108. That is, theinjection assembly 103, and portions thereof, is generally not movablewith the microneedle array holder 106 between the retracted H₁ and theextended position H₂. As a result, the injection assembly 101 can bedecoupled from and operate separately of the infusion assembly 103, eventhough both the injection assembly 101 and the infusion assembly 103 canform a portion of the overall apparatus 100, allowing each assembly tobe dedicated to their respective functions.

In some embodiments, the infusion assembly 103 (e.g., the shuttle 125and the cartridge 110) can be configured not to move independently ofthe housing 102 any appreciable amount in a direction oriented normal orsubstantially normal with respect to the skin surface 50. That is, insome embodiments, the infusion assembly 103 can be configured not tomove independently of the housing 102 toward or away from the skinsurface 50 by any appreciable amount. As in the illustrated embodiment,in some embodiments, the infusion assembly 103 may move toward the skinsurface 50 with the housing 102 as the apparatus 100 is actuated (e.g.,when an inverted actuator 104 is employed), without the infusionassembly 103 moving separately from the housing 102 in this direction.In some embodiments, the infusion assembly 103 can be located in aportion (e.g., an elongated portion, such as a handle or extension) ofthe apparatus 100 that can be pressed toward the skin surface 50 alongwith the remainder of the apparatus 100 when the apparatus 100 ispressed toward the skin surface 50 to actuate the actuator 104. Even insuch embodiments, the infusion assembly 103 can be configured not tomove relative to the housing 102 in a direction toward or away from theskin surface 50.

The first, retracted position H₁ and the second, extended position H₂can be spaced a distance from one another along an actuation axis A′(see FIGS. 3, 7 and 16), such that the microneedle array holder 106 ismovable along the actuation axis A′, e.g., relative to the housing 102and the actuator 104 (e.g., after the actuator 104 has been moved to itssecond position P₂), between the first, retracted position H₁ and thesecond, extended position H₂.

The actuation axis A′ can generally be oriented substantially normalwith respect to the skin surface 50 (and the first side 121 of theholder 106, as well as the first side 116 of the microneedle array 107when coupled to the holder 106), but this need not be the case. Rather,in some embodiments, the actuation axis A′ can be arcuate or defineotherwise nonlinear path(s), etc. The actuation axis A′ simply refers tomovement between the first, retracted position H₁ and the second,extended position H₂.

The actuator 104 can further include a base 133 that is configured to bepositioned toward the skin surface 50, and a cavity (or chamber, orrecess, or pocket, or bore) 134 that extends through the base 133 of theactuator 104 to form an opening 135 (see, e.g., FIG. 7) in the base 133of the actuator 104. The base 133 can be at least partially defined bythe outer portion 132 of the actuator 104, and the cavity 134 can be atleast partially defined by the inner portion 130 that is dimensioned tobe received in the cavity 114 of the housing 102.

As can be seen by comparing FIGS. 7 and 9, in some embodiments, theactuator 104 (e.g., the base 133 thereof) can be movable with respect tothe base 112 of the housing 102, such that when the actuator 104 is inthe first position P₁, an outermost surface (e.g., the base 133) of theactuator 104 can extend beyond the base 112 of the housing 102 by afirst distance d₁ (e.g., see FIG. 7); and when the actuator 104 is inthe second position P₂, the outermost surface of the actuator 104 eitherno longer extends beyond the base 112 of the housing 102 (e.g., is flushwith, or recessed relative to, the base 112), or the outermost surfaceof the actuator 104 extends beyond the base 112 of the housing 102 by asecond distance d₂ (e.g., see FIG. 9) that is less than the firstdistance d₁. That is, in some embodiments, the actuator 104 can bemovable between the first position P₁ and the second position P₂ withrespect to the base 112 of the housing 102, into and out of the opening115 formed in the base 112 of the housing 102. Said another way, in someembodiments, when the actuator 104 is in the first position P₁, at leasta portion of the actuator 104 can protrude from or through the opening115 in the base 112 of the housing 102 and can define a first surface(e.g., the base 133) configured to be coupled to the skin surface 50.Such a first surface can include a skin-contact adhesive 150, asdescribed below.

The configuration of the actuator 104 is shown by way of example only asbeing located on a skin-facing surface of the apparatus 100, i.e.,adjacent the base 112 of the housing 102. Said another way, the outer(engageable) portion 132 of the actuator 104 is shown as being locatedon and protruding from a lower portion (i.e., the second portion 122) ofthe housing 102. That is, the actuator 104 is an example of an ‘invertedactuator,’ as compared to conventional systems, where the actuator 104is located on an underside of the apparatus 100. Such a configurationallows for facile operation of the apparatus 100 and particularly allowsfor the actuator 104 to be moved from the first position P₁ to thesecond position P₂ in response to the apparatus 100 being pressed towardthe skin surface 50 by pressing on a non-skin-facing, or upper, portionof the apparatus 100. Such a non-skin-facing, or upper, portion of theapparatus 100 (e.g., of the housing 102) need not be located directlyopposite the actuator 104. That is, the non-skin-facing, or upper,portion can be located in an off-axis position with respect to a centrallongitudinal or actuation axis of the actuator 104. Such an ‘invertedactuator’ is further described in PCT Publication No. WO 2014/193729,which is incorporated herein by reference.

The term “off-axis” generally refers to a position, direction, or axisof movement, that is not aligned with the central longitudinal oractuation axis of the actuator 104. For example, the actuator 104 canmove from the first position P₁ to the second position P₂ in a firstdirection, along an actuation axis A″ (see FIG. 7), which, in theembodiment illustrated in FIGS. 1-25, is also its central longitudinalaxis. Such actuation or movement of the actuator 104 can be caused by aforce exerted along a second direction that is not directly opposite thesecond direction or that is not aligned with the actuation axis A″ ofthe actuator 104. Rather, such movement of the actuator 104 can becaused by a force that is oriented at an oblique angle with respect tothe actuation axis A″ of the actuator 104. In some embodiments, thesecond direction or axis can intersect the first direction or theactuation axis A″ of the actuator 104 (e.g., at an oblique angle), orthe second direction or axis can be parallel with respect to the centrallongitudinal axis of the actuator 104 without being directly in linewith the actuation axis A″.

By allowing for off-axis actuation of the apparatus 100, the apparatus100 can offer more reliable actuation, enhanced user comfort andenhanced ergonomics, for example, if the apparatus 100 can be actuatedwithout requiring that a user engage or manipulate a specific locationor element on the apparatus 100. For example, at least a portion (e.g.,the first (upper) portion 120 of the housing 102) can be configured tobe pressed toward the skin 50 using any portion of a hand, such as auser's palm or fist, as opposed to requiring the precise dexterity offinger manipulation. Such a configuration can provide an advantage, forexample, for arthritic and/or elderly patients. In addition, off-axisactuation allows for actuation of the apparatus 100 in a variety ofways, as opposed to only a single option, that are clearly understood bya user, e.g., by an intuitive design or configuration.

While the ‘inverted actuator’ 104 of the illustrated embodiment is shownas also providing the opening 135 through which the microneedle array107 will be deployed to impact and penetrate a skin surface, in someembodiments, an inverted actuator can still be employed, i.e., on anunderside or skin-facing side of the apparatus 100 and housing 102,without the actuator 104 also defining a cavity 134 or opening 135through which the microneedle array 107 and microneedle array holder 106move (as is the case in the illustrated embodiment, as described below).That is, in some embodiments, the actuator 104 can still be inverted butnot positioned directly adjacent the opening through which themicroneedles 108 extend when the microneedle array holder 106 is in itsextended position H₂. Particular advantages, however, can result fromemploying an actuator 104 such as that illustrated where the microneedlearray holder 106 is movable within the cavity 134 of the actuator 104 aswell, such as a compact design.

In some embodiments, as shown in the illustrated embodiment, theactuator 104 can be configured so as to be located only in a portion ofthe apparatus 100, which can localize the actuation of the apparatus 100to a precise area, even without requiring precise user manipulation toactuate the apparatus 100. For example, as shown, in some embodiments,the overall apparatus 100 can have or define a first footprint having afirst area, and the actuator 104 can have a second footprint having asecond area, and the second area can be less than the first area. Insome embodiments, the second area can be less than half (i.e., less than50%) of the first area. In some embodiments, the second area can be lessthan a quarter (i.e., less than 25%) of the first area.

As shown in FIGS. 1-6 and 24-25, the cover 113 can be configured tocover the opening 115 in the base 112 of the housing 102. As shown inFIGS. 3-6 and described in greater detail below with respect to FIGS. 24and 25, in some embodiments, the cover 113 can be a ‘dual cover’ thatincludes a first portion 140 configured to cover at least a portion ofthe base 112 of the housing 102 adjacent the opening 115, and a secondportion 142 configured to be at least partially received in the cavity114 of the housing 102 and further configured to cover the plurality ofmicroneedles 108 on the microneedle array 107. In embodiments such asthe illustrated embodiment that employ an ‘inverted actuator’ 104, thecover 113 can further be configured to cover the opening 135 to thecavity 134 of the actuator 104 (see, e.g., FIG. 3). The cover 113 (e.g.,the second portion 142 thereof) can be configured to maintain thesterility of the microneedles 108 and the fluid path 123. In embodimentsin which the microneedle array 107 will be deployed via the opening 135in the actuator 104, the cover 113 (e.g., the first portion 140 thereof)can also be configured to cover and protect the actuator 104 prior touse, and can be used to inhibit or prevent accidental prematureactuation of the actuator 104. In embodiments in which the microneedlearray 107 will deployed via the opening 115 in the housing 102 but notnecessarily the opening 135 in the actuator 104, the cover 113 (e.g.,the first portion 140 thereof) can be configured to cover and protect atleast the portion of the base 112 of the housing 102 that is configuredto be coupled to a skin surface. The cover 113 is further described inPCT Publication No. WO 2014/193727, which is incorporated herein byreference.

As shown in FIG. 5, in some embodiments, the base 133 of the actuator104 can include the skin-contact adhesive 150 (described in greaterdetail below), and the apparatus 100 can further include an optionalrelease liner 152 (described in greater detail below), which can protectthe skin-contact adhesive 150 prior to use and during assembly, storageand shipment of the apparatus 100. The release liner 152 can be removedprior to applying the apparatus 100 to skin. The release liner 152 canbe configured to release, or can be configured to present releasecharacteristics to, the skin-contact adhesive 150, so that the apparatus100 can be coupled to the release liner 152 during storage and shipment,and can be easily separated from the release liner 152 duringapplication of the apparatus 100. By way of example only, the releaseliner 152 can include a tab 155 (see FIGS. 4 and 5) positioned tofacilitate removing the release liner 152 from the skin-contact adhesive150 when desired. As shown, the tab 155 can include one or more folds153 to allow the tab 155 to be shortened during storage but lengthenedwhen desired to facilitate removal of the release liner 152.

In use, the release liner 152 can be removed (if employed) from theskin-contact adhesive 150, and the adhesive base 133 of the actuator 104can be coupled to the skin 50. Actuation of the actuator 104 can occurimmediately following coupling of the base 133 of the actuator 104 tothe skin 150 or even substantially simultaneously with coupling the base133 to the skin 150. The base 133 of the actuator 104 (or the base 112of the housing 102, if the skin-facing actuator 104 is not employed) canremain coupled to the skin 50 throughout injection and infusion. As aresult, in some embodiments, the apparatus 100 can be configured to be“worn” by a patient during infusion/injection of fluid into the skin 50.In such embodiments, the apparatus 100 may be directly applied to apatient's skin 50 to accommodate ambulatory movement while keeping themicroneedles 108 at an appropriate penetration depth(s). That is, evenin embodiments in which the housing 102 itself does not include theskin-contact adhesive 150, the housing 102 (i.e., the apparatus 100 as awhole, including the actuator 104, the housing 102, and the elements ofthe infusion assembly 103) can be configured to remain coupled to theskin surface 50 after the microneedle array 107 has punctured the skin50 and during infusion. For example, in such embodiments, the housing102 can be configured to be adhered to the skin 50 via the skin-contactadhesive 150 on the actuator 104.

In embodiments in which the actuator 104 is not located on an undersideor on a skin-facing portion of the apparatus 100 (or housing 102), thebase 112 of the housing 102 can include the skin-contact adhesive 150and optional release liner 152. In addition, any description hereinregarding positioning the base 133 of the actuator 104 on the skinsurface 50 can instead be interpreted to be referring to positioning thebase 112 of the housing 102 on the skin surface 50. Similarly, anydescription regarding movement of the microneedle array holder 106within the cavity 134 of the actuator 104 may still apply if theactuator 104 is not located on a skin-facing portion of the apparatus100, depending on the relative configuration of these components.Furthermore, in embodiments in which the actuator 104 is inverted asshown in the illustrated embodiment, the base 133 of the actuator 104can be configured to contact (and adhere to, via the skin-contactadhesive 150) the skin 50 when the apparatus 100 is positioned on theskin surface 50. In embodiments in which the actuator 104 is notinverted, the base 112 of the housing 102 can be configured to contact(and adhere to) the skin 50 when the apparatus 100 is positioned on theskin surface 50.

In some embodiments, as shown, the microneedle array holder 106 can belocated in and movable in the cavity 134 of the actuator 104 between theretracted position H₁ and the extended position H₂. As such, in someembodiments, the actuator 104 can be configured to at least partiallysurround the microneedle array 107 when the microneedle array 107 iscoupled to the holder 106, at least when the holder 106 is in theextended position H₂. In some embodiments, the actuator 104 can beconfigured such that at least a portion of the actuator 104 (e.g., theouter portion 132) surrounds the microneedle array 107 (and/or themicroneedle array holder 106) on all sides, or encircles the microneedlearray 107 (and/or the microneedle array holder 106), at least when themicroneedle array holder 106 is in the extended position H₂.

As shown in FIGS. 7 and 9, in embodiments in which the actuator 104 isinverted and located adjacent the same opening 115 through which themicroneedle array 107 will contact the skin 50, and when the actuator104 is in the first position P₁ and the microneedle array holder 106 isin the retracted position H₁, the base 133 of the actuator 104 can bepositioned a first distance x₁ from the first side (or base) 121 of themicroneedle array holder 106 (and/or the first side (or base) 116 of themicroneedle array 107)—see FIG. 7. When the actuator 104 is in thesecond position P₂ the base 133 of the actuator 104 can be positioned asecond distance x₂ from the first side (or base) 121 of the microneedlearray holder 106 (and/or the first side (or base) 116 of the microneedlearray 107)—see FIG. 9—and the second distance x₂ can be less than thefirst distance x₁. As a result, the distance between the base 133 of theactuator 104 and the first side 121 of the microneedle array holder 106(or the first side 116 of the microneedle array 107) can decrease whenthe actuator 104 is moved from the first position P₁ to the secondposition P₂.

By way of example only, in the embodiment illustrated in FIGS. 1-25, atleast a portion of the cavity 114 in the housing 102 can have the shapeof a cylindrical bore, at least a portion of the actuator 104 caninclude an annular cross-sectional shape (e.g., when the cross-sectionis taken substantially parallel with respect to the base 133), and theinner portion 130 of the actuator 104 can be substantially tubular inshape and be dimensioned to be received in the cylindrical bore-shapedcavity 114 of the housing 102. In addition, the cavity 134 defined atleast partially by the inner portion 130 of the actuator 104 can havethe shape of a cylindrical bore. By way of example only, the centrallongitudinal axes of the bore-shaped cavities 114 and 134 defined by thehousing 102 and the actuator 104, respectively, can be substantiallyaligned, and the actuation axis A′ (see FIGS. 3, 7 and 16) ofmicroneedle array holder 106 can also be substantially aligned with thecentral longitudinal axes of the cavities 114 and 134.

In some embodiments, the actuation axis A′ and the central longitudinalaxes of the cavities 114 and 134 may not all be exactly aligned but canbe substantially parallel with respect to one another. In someembodiments, the actuation axis A′ of the holder 106 can be orientedsubstantially parallel with respect to the actuation axis A″ of theactuator 104, as shown in the illustrated embodiment. Furthermore, insome embodiments, as shown, the actuation A′ of the holder 106 can besubstantially aligned (i.e., in line with) with the actuation axis A″ ofthe actuator 104.

When the microneedle array holder 106 is in the first, retractedposition H₁, the holder 106 can be recessed within the housing 102 andthe actuator 104, such that the holder 106 (and the microneedle array107, when coupled to the holder 106) does not extend beyond the base 112of the housing 102 or the base 133 of the actuator 104. The microneedlearray 107 can be movable with the holder 106 along the entire distancebetween the holder's retracted and extended positions H₁ and H₂. Thatis, when the microneedle array holder 106 is in the first, retractedposition H₁ and a microneedle array 107 is coupled to the holder 106,the microneedle array 107 can also be in a first, retracted position M₁(see, e.g., FIGS. 3, 7, 9 and 11), e.g., in which the microneedle array107 is recessed within the housing 102 and the actuator 104 such thatthe microneedle array 107 does not contact (or is not positioned tocontact) the skin surface 50 when the base 133 of the actuator 104 (orthe base 112 of the housing 102 in embodiments in which the actuator 104is located in a different location than adjacent the base 112 of thehousing 102) is positioned on the skin surface 50. The microneedle array107 can be housed within the cavity 114 of the housing 102 and thecavity 134 of the actuator 104, and can be recessed with respect to thebase 112 of the housing 102 and the base 133 of the actuator 104 in itsretracted position M₁.

Furthermore, when the microneedle array holder 106 is in the second,extended position H₂ and a microneedle array 107 is coupled to theholder 106, the microneedle array 107 can also be in a second, extendedposition M₂ (see, e.g., FIGS. 15-17 and 22), e.g., in which at least aportion of the microneedle array 107 is positioned to contact the skinsurface 50 when the base 133 of the actuator 104 is positioned on theskin surface 50.

When the microneedle array holder 106 and the microneedle array 107 arein their respective second positions H₂ and M₂, at least a portion ofthe microneedle array 107 (and, potentially, a portion of themicroneedle array holder 106) can extend beyond the base 133 of actuator104 (or the base 112 of the housing 102 if an inverted actuator 104 isnot employed). However, this need not be the case, and in someembodiments, it can be preferred for this not to be the case. Rather, insome embodiments, the microneedles 108 can be positioned close enough tothe base 133 of the actuator 104 (while still being recessed within thehousing 102 and the actuator 104 and without extending beyond the base133 of the actuator 104), such that when the base 133 is pressed ontothe skin surface 50, the skin 50 is caused to deform or dome up throughthe opening 135 of the actuator 104 and into the cavity 134 to aposition where the skin 50 is contacted by the microneedles 108.

Portions of the housing 102 defining the cavity 114 and/or portions(e.g., the inner portion 130) of the actuator 104 defining the cavity134 can retain and/or guide the microneedle array holder 106 fordisplacement along a path generally perpendicular to the base 133 of theactuator 104 (and/or the base 112 of the housing 102), as indicated byarrow A in FIG. 7. The actuation axis A′ of the microneedle array holder106 can be generally normal or perpendicular to that of the longitudinalaxis L of the apparatus 100. While in one exemplary embodiment, themotion of holder 106 may be at substantially 90 degrees with respect tothe base 133 (and/or the base 112), it will be appreciated that thegenerally normal path may deviate from 90 degrees to assume orientationsthat can penetrate deep enough to deliver an intended dosage.

The microneedle array holder 106 (and a microneedle array 107 coupledthereto) can be movable from the retracted position H₁ (and M₁) to theextended position H₂ (and M₂) by a first stored energy device 138 thatis actuatable to release its potential energy for applying force to themicroneedle array holder 106 in a direction generally normal to the base133 (and/or the base 112), for example, downwardly, toward the skinsurface 50. In some embodiments, such actuated force allows for movementof the holder 106 in a controlled manner, thereby ensuring applicationof the necessary forces for hollow microneedles 108 to penetrate theskin of a patient. As a result, the apparatus 100 can reliably andconsistently deliver the microneedle array 107 to the skin at a desiredimpact velocity, e.g., to achieve the desired depth(s) of penetration.

In some embodiments, the first stored energy device 138 can beactuatable to apply force to the holder 106 to achieve a velocity of themicroneedle array 107 before impact (i.e., before the microneedle array107 held by the holder 106 impacts a patient's skin) ranging frombetween about 2 and about 20 m/s. More typically, the microneedle array107 can strike a patient's skin at a velocity before impact ranging frombetween about 4 and about 12 m/s, in some embodiments, at a velocitybefore impact of at least 5 m/s, and in some embodiments, at a velocitybefore impact of about 6 m/s.

In some embodiments, the first stored energy device 138 can include abiasing element (e.g., a spring), and is shown as a coil spring by wayof example only in the illustrated embodiment. However, stored energydevices of the present disclosure can include at least one stored energydevice from a group consisting of: biasing elements (e.g., springs),propellants, chemicals, motors, electrical devices, and combinationsthereof.

The microneedle array holder 106 is biased downwardly in the apparatus100, toward its extended position H₁. As a result, the microneedle array107, when coupled to the holder 106 is also biased toward its extendedposition M₁. The microneedle array holder 106 is primed, or held underload or against the bias (e.g., when a biasing element is employed asthe stored energy device 138) when in the retracted position H₁, suchthat when the microneedle array holder 106 is released from being held,the stored energy device 138 will provide the forces to move themicroneedle array holder 106 to its extended position H₂, andparticularly, at a desired velocity.

In some embodiments, a portion of the actuator 104 can hold themicroneedle array holder 106 in its retracted position H₁ until theactuator 104 has been moved to its second position P₂, at which pointthe actuator 104 no longer holds the microneedle array holder 106, andthe microneedle array holder 106 is free to be driven by the storedenergy device 138.

However, in some embodiments, as shown in the illustrated embodiment, anintermediate component, i.e., between the actuator 104 and the holder106, can be actuated to move (or be released) by moving the actuator 104to its second position P₂, and when that intermediate component isactuated or allowed to move, it moves to a position in which it nolonger retains the holder 106 in its retracted position H₁, and themicroneedle array holder 106 is free to be driven by the stored energydevice 138. As a result, in some embodiments, the microneedle arrayholder 106 is held within the housing 102 in its retracted position H₁by an element, component or structure of the apparatus 100 other thanthe actuator 104.

In the illustrated embodiment, that intermediate component is an elementof the infusion assembly 103, namely, the shuttle 125. The shuttle 125can be movable (e.g., substantially along the longitudinal axis L of theapparatus 100) between:

-   -   (i) a first, non-infusing, position S₁ (see, e.g., FIGS. 3, 4        and 7-10) in which the reservoir 111 of the cartridge 110 is not        in fluid communication with the fluid path 123 (i.e., in which        the cartridge 110 is fluidly isolated), and    -   (ii) a second, infusing, position S₂ (see, e.g., FIGS. 17        and 22) in which the reservoir 111 of the cartridge 110 is in        fluid communication with the fluid path 123.

As a result, in some embodiments, movement of the actuator 104 to itssecond position P₂ (i.e., “actuation” of the actuator 104) can actuateboth (i) movement of the shuttle 125 (i.e., the cartridge 110) to itssecond position S₂ and movement of the microneedle array holder 106 tothe extended position H₂.

Because the shuttle 125 of the illustrated embodiment is configured tohold and carry the cartridge 110, the first and second position S₁ andS₂ of the shuttle 125 also define positions of the cartridge 110. As aresult, the positions of the shuttle described herein can also refer topositions of the cartridge 110.

The shuttle 125 can be primed or held under a load in its first positionS₁ and can be biased toward its second position S₂, such that when theshuttle 125 is released by the actuator 104, the shuttle is free to moveand begins moving toward its second position S₂. Employing the separateshuttle 125 that carries the cartridge 110 and operates intermediatelybetween the actuator 104 and the microneedle array holder 106 canprovide a sequence of events that ensures a sufficient delay betweenimpact (i.e., movement of the microneedle array holder 106 to itsextended position H₂) and infusion (e.g., at least when the shuttle 125is moved to its second position S₂ where fluid communication isestablished between the reservoir 111 and the fluid path 123). That is,the microneedle array holder 106 can be moved to its extended positionH₂ before the shuttle 125 has completed its movement to its secondposition S₂. In some embodiments, as is the case in the illustratedembodiment, the shuttle 125 can begin moving to its second position S₂before the microneedle array holder 106 may reach its extended positionH₂, but the apparatus 100 can be configured such that the shuttle 125will not have fully reached its second position S₂ (i.e., the point ofestablishing fluid communication between the cartridge 110 and the fluidpath 123) before the microneedle array 107 has punctured the skin 50.

Said another way, even though the actuator 104 actuates movement of boththe shuttle 125 and the microneedle array holder 106, the microneedlearray holder 106 can be in its extended position H₂ when the shuttle 125reaches its second position S₂, such that there is a lag or delaybetween when the microneedle array 107 is inserted into the skin 50 andwhen the reservoir 111 is placed in fluid communication with themicroneedle array 107. If this were not the case, active agent couldbegin leaking out of the microneedles 108 prior to the microneedles 108penetrating the skin 50. In some embodiments, this lag can accommodate aperiod of time in which the microneedle array 107 may undergo someundulating motion as it impacts the skin 50, which can be about 8 toabout 10 milliseconds. Generally, it can be advantageous to providefluid communication between the fluid path 123 and the cartridge 110after the microneedle array 107 (and holder 106) has reached a steadystate condition and is no longer bouncing on the skin surface 50.

The shuttle 125 can be configured to movable between its first positionS₁ and its second position S₂ in a direction or along an axis that isoriented at a non-zero angle with respect to the actuation axis A′ ofthe holder 106 and/or the actuation axis A″ of the actuator 104. Thatis, in some embodiments, he microneedle array holder 106 can be movablebetween the retracted position H₁ and the extended position H₂ along afirst axis (i.e., its actuation axis A′), the actuator 104 can bemovable between the first position P₁ and the second position P₂ along asecond axis, and the shuttle 125 can be movable between the firstposition S₁ and the second position S₂ along a third axis, and the thirdaxis can be oriented at a non-zero angle with respect to one or both ofthe first axis and the second axis. Particularly, in embodimentsemploying a low profile configuration in which the shuttle 125 can beconfigured to move in a direction substantially parallel to the skinsurface 50, which can also be generally along the longitudinal axis L insome embodiments, and the third axis can be oriented substantiallyperpendicularly with respect to one or both of the first axis and thesecond axis.

The shuttle 125 can be configured to interact with the microneedle arrayholder 106 to retain the holder 106 in its retracted position H₁ untilthe shuttle 125 reaches an intermediate position (i.e., a third positionS₃—see, e.g., FIG. 13) in between the first position S₁ and the secondposition S₂ in which the microneedle array holder 106 is released frombeing held in its retracted position H₁ by the shuttle 125. FIGS. 11 and12 show the shuttle 125 after it has begun to move from its firstposition S₁, but before it has reached the third position S₃ in whichthe holder 106 is released.

Movement of the shuttle 125 between its first and second positions S₁and S₂ can be accomplished or driven by one or more stored energydevices. In the illustrated embodiment, two stored energy devices areused to fully move the shuttle 125 from the first position S₁ to thesecond position S₂. By way of example, in the illustrated embodiment, asecond stored energy device 144 (see FIGS. 3, 6, 7, 9, 11, 13, 16, 17and 22) can initiate movement of the shuttle 125, e.g., to move theshuttle 125 from the first position S₁ to the third position S₃, wherethe microneedle array holder 106 can be released from its retractedposition H₁. By way of further example, in the illustrated embodiment, athird stored energy device 146 (see FIGS. 3, 6, 7, 9 and 11, 13, 16, 17and 22) can complete movement of the shuttle 125 to its second positionS₂ wherein the reservoir 111 of the cartridge 110 is in fluidcommunication with the fluid path 123, and can further initiate andcomplete infusion of an active agent from the reservoir 111 of thecartridge 110, into the fluid path 123, and out the hollow microneedles108.

The cartridge 110 can include a piston 148 that is movable in thereservoir 111 of the cartridge 110 to force the active agent out of thecartridge 110, into the fluid path 123, and out the hollow microneedles108. The piston 148 can be in a sliding and sealing relationship withrespect to interior walls of the cartridge 110. This can provideadequate sealing for a fluid stored in an interior variable volumechamber formed between the piston 148 and an openable end 151 of thecartridge 110. The piston 148 can be moved or pressed in the cartridge110 by a plunger 149 that can be coupled to, and movable with, theshuttle 125 and the cartridge 110, until the shuttle 125 reaches itssecond position S₂, after which the plunger 149 can be movable withrespect to the housing 102, the shuttle 125, the cartridge 110, etc. todrive the piston 148 to dispense the active agent. That is, in someembodiments, the infusion assembly 103 can be configured such that thepiston 148 (and the plunger 149) is not movable in the reservoir 111with respect to the shuttle 125 until the shuttle is in its secondposition S₂. Said another way, in some embodiments, the infusionassembly 103 can be configured such that the piston 148 is inhibited orprevented from movement to its second position until the shuttle 125 isin its second position S₂.

The piston 148 and the plunger 149 can be movable together between (i) afirst (non-dispensing or non-delivery) position in which the activeagent is not being forced out of the reservoir 111 and into the fluidpath 123 (i.e., in which the active agent is contained within thereservoir 111); and (ii) a second, dispensed, position in which theactive agent is being forced out of the reservoir 111 and into the fluidpath 123.

Given the volume variability of the reservoir 111 of the cartridge 110,the cartridge 110 can be configured to accommodate any intended dosagevolume. Such a cartridge 110 may be of the type wherein pre-filled drugsare ready-to-be used. The cartridge 110 may be of the kind thatsatisfies standards, including international standards, such as theInternational Organization for Standards (ISO). In addition, a glasscylinder can be employed as the cartridge 110, which can be relativelyeasy to clean and sterilize.

The present disclosure also contemplates the use of valve mechanisms foropening the openable end 151 of the cartridge 110 for allowingtransferring of an active agent to the fluid path 123. For example, avalve member retained by the cartridge 110 may be opened from a fluidblocking or closed condition by having it cooperate with structure (notshown), such as a cannula, as the two are brought into operativeengagement. Suitable valve mechanisms include, but are not limited to,those disclosed in International Publication No. WO2005/018705 toCindrich et al.

Referring back to the piston 148, it is adapted to travel along a lengthof reservoir 111 (e.g., which can be oriented substantially along thelongitudinal axis L) until the active agent is completely (or nearlycompletely) forced or expressed therefrom. Typically, the piston 148 maybe made of materials that seal against the body of cartridge 110, butare also inert with respect to the active agent. For example, purifiedelastomeric materials such as halobutyl rubber and silicone rubbermaterials may be typically used for such pistons, but other materialssuch as non-elastomeric materials are also contemplated. In addition,the piston 148 can be made of diverse materials including laminatedconstructions. While the illustrated embodiment uses one kind of piston,others can be utilized, including those contoured to substantially matchthe interior shape of the openable end 151.

Other means to reduce void space in the cartridge are contemplated. Forexample, small spherical objects can be included in the reservoir 111.When the piston 148 moves forward and pushes the active agent out of thecartridge 110, the small spherical objects can also be pushed forwardinto the neck of the cartridge 110 and around the piercing element 175.The spherical objects are preferably larger than the fluid path 123 inthe piercing element 175 so as to avoid plugging the fluid path 123.Instead, the spherical objects can pack around the piercing element 175and displace active agent in the cartridge neck space. The sphericalobjects can be made of metal, plastic, glass, ceramic, or other materialthat is compatible with the active agent in the reservoir 111.

The cartridge 110 has longitudinal axis that can be generally orientedalong the longitudinal axis L of the apparatus 100 and/or that can beoriented generally parallel to the skin 50 in use. In other embodiments,the cartridge 110 can be disposed at non-zero angles relative to theskin 50. In embodiments wherein a low profile for the apparatus 100 (orat least the infusion assembly 103 thereof) is desired, the longitudinalaxis of the cartridge 110 can be generally parallel to the major plane(e.g., of the first side 116) of the microneedle array 107 (when coupledto the microneedle array holder 106). The cartridge 110 can be a glassdrug cartridge (e.g., that is transparent). Such a glass drug cartridgemay be of a commercially available type, such as from Schott NorthAmerica, Elmsford, N.J., USA, and West Pharmaceutical Services, Inc. ofLionsville, Pa., USA. Other kinds of cartridges having similarproperties are well within the scope of the disclosure.

When made of glass, the cartridge 110 may also be advantageous in regardto enhancing the versatility of the delivery systems of the presentdisclosure. One potential advantage is that the cartridge 110 canconform to the sizes and shapes already familiar in the pharmaceuticalfield that can be, e.g., readily fillable using commercial equipment. Inaddition, because the cartridge 110 may be packaged separately from theapparatus 100, users may be able to use custom reservoirs and easilyinstall them in the apparatus 100 at the point of use. As shown in FIG.6, in some embodiments, a door or cover 147 can be employed to allowdirect access to the location of the infusion assembly 103 in which thecartridge 110 can be positioned. Moreover, by being able to use knowndrug cartridges, patients are able to use a wide variety of drugs anddosages dispensed in a manner particularly tailored to them and not bedependent on a manufacturer of the dispensers having fixed cartridges.

A typical glass drug cartridge that may be employed with the apparatusesof the present disclosure may have dimensions that range from 2 cm toabout 8 cm in terms of their length, and may have inner diameters thatrange from 4 mm to 12 mm. More typically, the lengths may range from 4cm to 6 cm, and the inner diameters from 6 mm to 10 mm. The presentdisclosure contemplates other dimensions depending on, for example, thevolume of the active agent to be delivered. While a transparent glassdrug cartridge may be used, other materials may also be used. Thematerials and construction of the cartridge 110 are generally compatiblewith the desired active agent to be dispensed and able to withstand thepressures generated during use.

In some embodiments, the volume of the active agent to be delivered orinfused can be at least 0.1 mL, in some embodiments, at least 0.2 mL,and in some embodiments, at least 0.5 mL. In some embodiments, thevolume can be no greater than 20 mL, in some embodiments, no greaterthan 10 mL, in some embodiments, no greater than 5 mL, and in someembodiments, no greater than 3 mL. In some embodiments, the volume canrange from 0.1 mL to 20 mL, in some embodiments, from 0.1 mL to 10 mL,and in some embodiments, from 0.1 to 5 mL. In some embodiments, thevolume can range from 0.5 mL to 3 mL.

By way of example only, in the illustrated embodiment, the same thirdstored energy device 146 that completes the movement of the shuttle 125to its second position S₂ can also initiate and complete the infusionprocess, i.e., to initiate and complete movement of the plunger 149 andthe piston 148, accordingly, to dispense the active agent.

In some embodiments, the second and third stored energy devices 144 and146 can each include a spring or biasing element, and each is shown as acoil spring by way of example only in the illustrated embodiment.However, any of the above stored energy devices can be employed for eachof the second and third stored energy devices 144 and 146. Inembodiments in which a biasing element is employed, the shuttle 125 canbe primed or held under load, e.g., against the bias of the biasingelements 144 and 146 when the shuttle is in the first position S₁.

That is, the shuttle 125 can be biased in or toward its second positionS₂. For example, the shuttle 125 can be biased by one or both of thesecond stored energy device 144 and the third stored energy device 146,e.g., if one or both of the second and third stored energy devices 144and 146 includes a biasing element. The shuttle 125 can be maintained inits first position S₁ until the actuator 104 has been moved to itssecond position P₂. By way of example, in the illustrated embodiment,the actuator 104 includes a portion that maintains the shuttle 125 inits first position S₁ until the actuator 104 has been moved to itssecond position P₂.

Specifically, in some embodiments, as shown in FIGS. 8, 10 and 12, theactuator 104 can include one or more shuttle stops (or catches, ordetents) 154 that can be movable with the actuator 104 when the actuatoris moved between its first and second positions P₁ and P₂. The apparatus100 is generally symmetrical about the longitudinal axis L. As such, theillustrated embodiment employs two shuttle stops 154—one on each side ofthe apparatus 100; however, only one is shown in FIGS. 8, 10 and 12. Itshould be understood, however, that in some embodiments, the apparatus100 can include only one shuttle stop 154. In embodiments in which morethan one shuttle stop 154 is employed, it should be understood that thedescription herein can equally apply to additional stops.

The shuttle stop 154 is configured to abut and/or engage at least aportion of the shuttle 125. As a result, the shuttle stop 154 can becoupled to or formed by at least a portion of the actuator 104, and canbe movable, with the actuator 104, between:

-   -   (i) a first position T₁ with respect to the housing 102, the        shuttle 125 and the microneedle array holder 106 (see FIG. 8) in        which the shuttle stop 154 is positioned to engage at least a        portion of the shuttle 125 to hold the shuttle 125 in its first        position S₁, and    -   (ii) a second position T₂ with respect to the housing 102, the        shuttle 125 and the microneedle array holder 106 (see FIGS. 10        and 12) in which the shuttle stop 154 is no longer positioned to        engage at least a portion of the shuttle 125 to hold the shuttle        125 in its first position S₁, such that when the shuttle stop        154 is in the second position T₂, the shuttle 125 is free to        move to its second position S₂, e.g., by the second and third        stored energy devices 144 and 146.

In FIGS. 7 and 8, the actuator 104, the shuttle 125, the microneedlearray holder 106, and the piston 148 (and the plunger 149) are all intheir respective first positions. In these respective first positions,the shuttle 125, the microneedle array holder 106, and the piston 148(and the plunger 149) can be primed or held under a load, ready to befired, i.e., driven by the stored energy devices 138, 144 and/or 146.

In FIGS. 9 and 10, the actuator 104 is in its second position P₂ and theshuttle stop 154 is in its second position T₂, but the shuttle 125 hasnot yet begun to move toward its second position S₂. In FIGS. 11 and 12,the actuator 104 is in its second position P₂ and the shuttle stop 154is in its second position T₂, and the shuttle 125 has begun to movetoward its second position S₂, but the microneedle array holder 106 hasnot yet been released from its retracted position H₁.

As shown in FIGS. 8, 10 and 12, the shuttle 125 can include one or moreextensions, prongs or projections 156 that are each configured to engageand interact with a shuttle stop 154. The extensions 156 are shown byway of example as lateral extensions that extend along the lateral sidesof the apparatus 100 and are elongated generally along the longitudinalaxis L. Each extension 156 includes a first portion (or surface, e.g., aside or front surface in the illustrated embodiment) that can be notchedor include a flange configured to engage the shuttle stop 154 of theactuator 104 until the actuator 104 has been moved out of engagementwith the shuttle 125, e.g., until the actuator 104 has been moved to thesecond position P₂, thereby moving the shuttle stop 154 to its secondposition T₂.

Each extension 156 can further include a second portion (or surface,e.g., an upper surface in the illustrated embodiment) that can beconfigured to engage with the shuttle stop 154 after the actuator 104has been moved to its second position P₂ so as to maintain the actuator104 in the second position P₂ after it has been moved to its secondposition P₂. As a result, as the actuator 104 is moved to its secondposition P₂, the shuttle 125 gets released; and the shuttle 125 can beconfigured such that as the shuttle 125 moves toward its second positionS₂, the shuttle 125 catches the actuator 104 and holds the actuator 104in its second position P₂.

Such a configuration can inhibit the actuator 104 from being forced backtoward its first position P₁ after actuation, e.g., which couldpotentially dislodge the microneedles 108 from the skin 50 during use.Accordingly, each shuttle stop 154 can include a first portion (orsurface, e.g., a side or rear surface in the illustrated embodiment)configured to inhibit movement of the shuttle 125 from its firstposition S₁ and a second portion (or surface, e.g., a lower surface inthe illustrated embodiment) configured to inhibit movement of theactuator 104 from its second position P₂ once the actuator 104 has beenmoved to its second position P₂. However, this arrangement andinteraction between the shuttle 125 and the actuator 104 is shown by wayof example only. In some embodiments, the shuttle stop 154 on theactuator 104 can be configured to engage a different element when in itssecond position P₂ to maintain the actuator 104 in its second positionP₂ after it has been moved to its second position P₂.

As shown, e.g., in FIGS. 4, 6 and 7-13, in some embodiments, themicroneedle array holder 106 can include one or more extensions orprongs 158 configured to engage one or more holder stops 160 on theshuttle 125. Similar to the shuttle stop 154 on the actuator 104, theholder stop 160 is movable with the shuttle 125, between:

-   -   (iii) a first position R₁ with respect to the housing 102, the        actuator 104, and the microneedle array holder 106 (see FIGS.        7-10) in which the holder stop 160 is positioned to engage at        least a portion of the microneedle array holder 106 (i.e., the        extension 158) to hold the microneedle array holder 106 in its        retracted position H₁, and    -   (iv) a second position R₂ with respect to the housing 102, the        actuator 104, and the microneedle array holder 106 (see FIG. 13)        in which the holder stop 160 is no longer positioned to engage        at least a portion of the microneedle array holder 106 to hold        the microneedle array holder 106 in its retracted position H₁,        such that when the holder stop 160 is in the second position R₂,        the microneedle array holder 106 is free to move toward its        extended position H₂, e.g., by the first stored energy device        138.

FIGS. 11 and 12 illustrate the shuttle 125 before it has quite reachedits intermediate third position S₃ in which the microneedle array holder106 is released and able to move toward its extended position H₂, whichis shown in FIG. 13. As mentioned above and is described in greaterdetail below with respect to FIGS. 14 and 15, FIG. 13 illustrates anoptional dampened position of the holder 106, before the holder 106 hasfully reached its extended position H₂, which is shown in FIGS. 15-17and 22.

The holder stop(s) 160 on the shuttle 125 can be coupled to or formed bya portion of the shuttle 125. By way of example only, the extension 158on the holder 106 is shown as being a vertical extension or projection.The extension 158 can be notched or include a flange (e.g., such thatthe extension 158 includes a lower surface) that is configured to abutthe holder stop 160 (e.g., an upper surface thereof). The holder stop160 can extend a predetermined distance along the longitudinal axis L ofthe apparatus 100, such that when the holder stop 160 has moved to itssecond position R₂, the extension 158 on the holder 106 has cleared theholder stop 160, is no longer in engagement with the holder stop 160,and the holder 106 is free to be driven by the first stored energydevice 138 to its extended position H₂. By further way of example, theholder stop 160 can be formed or defined by one or more extensions,prongs or projections 162. Specifically, in the illustrated embodiment,the shuttle 125 includes two extensions 162 that extend generally alongthe longitudinal axis L of the apparatus 100 and include a lower ledgeor flange that includes an upper surface that defines the holder stop160. In the illustrated embodiment, the holder stop 160 is specificallyformed by two of such ledges that the extension 158 of the holder 106rests on, or is forced against, when the holder 106 is held under loadin its retracted position H₁. That is, the extension 158 and the holderstop 160 slide relative to one another as the shuttle 125 is moved inthe housing 102 generally along the longitudinal axis L of the apparatus100 toward its second position S₂, until the holder stop 160 reaches itssecond position R₂ (i.e., until the shuttle 125 reaches its thirdposition S₃, located intermediately between its first position S₁ andits second position S₂).

As shown in FIGS. 6 and 14-15, in some embodiments, the apparatus 100can include one or more dampeners 163 positioned between the microneedlearray holder 106 and the actuator 104 (or the housing 102 in embodimentsin which the holder 106 is not moving to its extended position H₂adjacent the inverted actuator 104). The dampeners 163 can be configuredto at least partially deform in response to the inertia of themicroneedle array holder 106 as the holder 106 is driven by the firststored energy device 138 to its extended position H₂, thereby dampeningor slowing the holder 106 as it comes to a stop in its extended positionH₂. In the illustrated embodiment, the dampener 163 includes a wireformed into an incomplete circle (see FIG. 6) positioned in a recesswithin the cavity 134 of the actuator 104 and located between the base133 of the actuator 104 and an underside of the holder 106 (see FIG.14). FIG. 15 illustrates the holder 106 at the end of its travel (i.e.,with the holder 106 fully in its extended position H₂ and themicroneedle array 107 fully in its extended position M₂), with its guiderails resting on the ends of guides formed within the actuator 104. Thedampener 163 in FIG. 15 has been deformed and forced into a lower recess164 by the holder 106. In the illustrated embodiment, the recess 164into which the dampener 163 is forced is defined by the actuator 104;however, in embodiments in which the holder 106 does not travel in theactuator 104, such a recess could be provided by the housing 102 oranother element of the apparatus 100. The illustrated dampener 163 andrelative configuration between the holder 106 and the actuator 104 areshown by way of example only; however, any energy or shock absorbingelement or material can be employed and other configurations arepossible and within the spirit and scope of the present disclosure.

While the microneedle array 107 impacts the skin 50, the shuttle 125continues to travel along the longitudinal axis L toward its secondposition S₂ (as shown in FIGS. 17 and 22). In the illustratedembodiment, as shown in FIGS. 13, 16, 17 and 22, the indicator 126 caninclude a first portion (or “main body”) 126 a and a second portion (or“tail”) 126 b that are configured to be removably coupled together,e.g., by one or more latches or detents 166.

The second stored energy device 144 (e.g., a spring) can be locatedwithin one or more retaining walls or tubes 168 (see, e.g., FIG. 13),which are provided by, or fixedly coupled to, the housing 102. By way ofexample, the retaining wall 168 is generally tubular, generallycentrally located in the housing 102 with respect to the shuttle 125 andthe indicator 126, and oriented generally along the longitudinal axis L.The retaining wall 168 can define a recess (or bore or chamber) 173,e.g., which can receive at least a portion of the second stored energydevice 144. In addition, the first indicator portion 126 a and thesecond indicator portion 126 b of the illustrated embodiment eachinclude inner (e.g., concentric and forwardly-projecting) walls (orprongs or projections) 170 a and 170 b, respectively, that are removablycoupled together (e.g., at their respective front ends) via the latch166 and together define a generally tubular recess 172 (see FIG. 13)configured to receive the retaining wall 168. By way of example, in theillustrated embodiment, the inner wall 170 b of the second indicatorportion 126 b is formed by a series of (circumferentially-spaced) prongsconfigured to be arranged about the inner circumference defined by theinner wall 170 a of the first indicator portion 126 a when the first andsecond indicator portions 126 a and 126 b are coupled together via thelatch 166. Accordingly, the inner wall 170 a of the first indicatorportion 126 a can include a series of notches or openings configured toreceive at least a portion of the inner wall 170 b, i.e., the portion(s)of the one or more prongs forming the one or more latches 166.

As the shuttle 125, along with the indicator 126, is initially movedfrom its first position S₁ by the second stored energy device 144, theinner walls 170 a and 170 b, removably coupled by the latch 166, slideor ride along the retaining wall 168 (and the retaining wall 168 isreceived within the recess 172 defined by the inner walls 170 a and 170b). At this stage, the retaining wall 168 inhibits the inner walls 170 aand 170 b from flexing or deflecting inwardly, thereby maintaining thelatch 166 in a closed or latched configuration and maintaining the innerwalls 170 a and 170 b coupled together.

The retaining wall 168 only extends (e.g., along the longitudinal axis Lof the apparatus 100) a relatively short distance forward from a rearwall 169 of the housing 102. Thus, as the shuttle 125 and the indicator126 continue to travel in the housing 102, the inner walls 170 a and 170b of the first indicator portion 126 a and the second indicator portion126 b move beyond the retaining wall 168 to a location where the innerwalls 170 a and 170 b can flex relative to one another. Particularly, inthe illustrated embodiment, at this point, the inner wall 170 b of thesecond indicator portion 126 b is free to flex inwardly, i.e., relativeto the inner wall 170 a of the first indicator portion 126 a. The thirdstored energy device 146 can now provide (or assist in providing) theenergy necessary to overcome the latch or detent 166 to allow the firstand second indicator portions 126 a and 126 b to become separated, asshown in FIG. 16. The third stored energy device 146 is positioned toengage at least a portion of the second indicator portion 126 b to causethe second indicator portion 126 b to move in a direction opposite theshuttle 125 and the first indicator portion 126 a, e.g., rearwardly inthe housing 102 toward the rear wall 169, with the inner wall 170 briding along and receiving the retaining wall 168.

In some embodiments, at least a portion of the indicator 126 can be inan abutting relationship with the shuttle 125. For example, as shown inFIG. 13, prior to the shuttle 125 reaching its second position S₂, thesecond indicator portion 126 b can be in abutting relationship with arear end of the first indicator portion 126 a and a rear end of theshuttle 125, i.e., until the first indicator portion 126 a and thesecond indicator portion 126 b are separated.

After the first indicator portion 126 a and the second indicator portion126 b are separated, the second stored energy device 144 and the thirdstored energy device 146 are both positioned to continue to move theshuttle 125 and the first indicator portion 126 a in the housing 102toward the second shuttle position S₂. The second stored energy device144 is positioned to continue pushing the plunger 149, while the thirdstored energy device 146 is positioned to move the first indicatorportion 126 a, which is coupled to the plunger 149 (e.g., via the innerwall 170 a). The plunger 149 is positioned to contact and push thepiston 148 to pressurize the reservoir 111 of the cartridge 110, and afront end (i.e., the openable end 151) of the cartridge 110 ispositioned to contact an inner surface of the shuttle 125 to continue todrive the shuttle 125 to its second position S₂ (as shown in FIGS. 17and 22). In some embodiments, the fluid within the cartridge 110 is notpressurized until this step, i.e., until the apparatus 100 is actuatedand the resulting series of events includes pressurizing the cartridge110. For example, in the illustrated embodiment, the second storedenergy device 144 is responsible for launching the shuttle 125 (and thecartridge 110) toward its second position S₂, and the third storedenergy device 146, which is configured to provide greater forces thanthe second stored energy device 144, completes the movement of theshuttle 125, pressurizes and energizes the cartridge 110, and moves thepiston 148 in the reservoir 111 of the cartridge 110.

The second indicator portion 126 b that is configured to be removablycoupled to the first indicator portion 126 a is described as being aportion of the indicator 126 by way of example only. This element caninstead be described as a portion of the shuttle 125, or as a separateelement altogether that is configured to be removably coupled to atleast one of the indicator 126 and the shuttle 125.

By way of example only, the plunger 149 of the illustrated embodiment iscoupled to or provided by (e.g., integrally formed with) the indicator126, such that the indicator 126 includes (i) an inner portion 185(i.e., positioned to comprise or be coupled to the plunger 149), atleast a portion of which is responsible for engaging and moving thepiston 148 in the cartridge 110; and (ii) an outer portion 187configured to ride along an outer surface or wall 188 of the shuttle 125to be visible through the window 124 to display the progress of theinfusion of the active agent (see FIGS. 13, 16, 17 and 22).Specifically, in the illustrated embodiment, the outer portion 187 ofthe indicator 126 is dimensioned to be received between a retaining wall105 of the housing 102 and the outer surface or wall 188 of the shuttle125. That is, the outer portion 187 of the indicator 126 can bedimensioned to receive at least a portion of the shuttle 125, such thatafter the shuttle 125 has been moved to its second position S₂, theindicator 126 can be movable with respect to the shuttle 125.

Furthermore, in the illustrated embodiment, the plunger 149 includes ordefines an internal recess or chamber 171, and the second stored energydevice 144, e.g., in the case where a spring is employed as the secondstored energy device 144, can be dimensioned to be at least partiallyreceived in the recess 173 defined by the retaining wall 168 and extendat least partially into the internal chamber 171 to drive or bias theplunger 149 away from the rear wall 169 of the housing 102.

Additionally, in the illustrated embodiment, the outer portion 187 ofthe indicator 126 includes a first outer recess or chamber 190 definedbetween an inner surface or wall of the outer portion 187 of theindicator 126 and the outer surface or wall 188 of the shuttle 125, thefirst outer recess 190 opening rearwardly. The first outer recess 190can be dimensioned to receive the third stored energy device 146 (e.g.,when a spring is employed as the third stored energy device 146). Assuch, the third stored energy device 146 can be positioned to drive orbias a forward or front end of the indicator 126 forward in the housing102, away from the rear wall 169 of the housing 102. In someembodiments, as shown, the outer portion 187 of the indicator 126 canfurther include a second outer recess 191 dimensioned to receive atleast a portion of the shuttle 125, the second outer recess 191 openingforwardly.

Furthermore, in some embodiments, as shown, the inner portion 185 of theindicator 126 can also include or define an inner recess or chamber 192dimensioned to receive at least a portion of the cartridge 110.Particularly, the inner recess 192 can receive a closed end of thecartridge 110 (e.g., that includes the piston 148), for example, in apress-fit engagement. As shown, the cartridge 110 can be positioned inthe inner recess 192 such that the piston 148 abuts a forward or frontend of the plunger 149.

As shown in FIG. 17, the combined forces provided by the second storedenergy device 144 and the third stored energy device 146 can completethe movement of the shuttle 125 to its second infusing position S₂ wherethe reservoir 111 of the cartridge 110 is placed into fluidcommunication with the fluid path 123. By way of example, as describedabove, the fluid path 123 can include or be coupled to the piercingelement 175 (e.g., a hollow needle) that, by way of example only, canremain fixed with respect to the housing 102 and the shuttle 125. By wayof further example, the cartridge 110 can be fitted with a cap 176 and aseptum 177 that is accessible via the cap 176. In some embodiments, thecartridge 110 can include a glass cylinder, and the open, or openable,end 151 can be closed and sealed by the cap 176. The cap 176 can includea metallic cap, such as an aluminum cap, that can be crimped to the openend 151 of the cartridge 110 in a know manner. The cap 176 can hold theseptum 177 that sealingly closes the otherwise open end 151 of thecartridge 110.

The septum 177 may be made of many different materials including thosetypically used with reservoirs (e.g., drug cartridges). The septum 177may be made of a pierceable and resealable elastomeric seal or septumthat is securely mounted, with or without being crimped, across the openend 151 of the cartridge 110. In some embodiments, the septum 177 (e.g.,formed of an elastomer) may be crimped onto an end of the cartridge 110with a malleable cap 176, e.g., formed of aluminum. Other similar septummaterials and modes of securing it to the open end 151 of the cartridge110 may be used. For example, a septum molded into the body of acylinder may be used, such as the CZ series available from WestPharmaceutical Services, Inc, Lionville, Pa., a cap, such as a standardsyringe luer cap, or a molded end thin enough to be pierced. Suitablematerials are subject to piercing with sufficient piercing force andmaintain a seal once pierced. As noted above, the septum 177 can bepierced during use and seal around the piercing element 175 with enoughforce to prevent leakage during pressurization and transfer of theactive agent from the reservoir 111. Certain septum materials allow theseptum 177 to reseal following withdrawal of the piercing element 175after use. The present disclosure envisions unsealing or opening theotherwise closed septum 177 by a variety of approaches.

When the shuttle 125 is moved to its second position S₂, the piercingelement 175 can pierce or puncture the septum 177, thereby placing thefluid path 123 (i.e., via the interior of the piercing element 175) influid communication with the reservoir 111 of the cartridge 110, asshown in FIG. 17. At this point, as further shown in FIG. 17, the openend 151 of the cartridge 110 (e.g., and the cap 176) abuts a base 178 ofthe piercing element 175, which defines the second position S₂ of theshuttle 125. As a result, the shuttle 125 and the cartridge 110 come toa stop within the housing 102. The third stored energy device 146, anend of which is positioned to engage an end of the indicator 126 can nowtransfer its remaining stored energy to moving the indicator 126 (i.e.,the first indicator portion 126 a), along with the plunger 149, to drivethe piston 148 within the reservoir 111 and force the active agent intothe fluid path 123, via the piercing element 175, to the hollowmicroneedles 108. FIG. 18 shows the indicator 126 beginning to bedisplayed through the window 124 of the housing 102 as the infusionprocess begins. The indicator 126 can be colored or otherwiseconspicuous relative to the other components of the apparatus 100 to beclearly visible to a user.

In the illustrated embodiment, the first side 121 of the holder 106 andthe second side 118 of the microneedle array 107 can be configured to bespaced a distance apart when the microneedle array 107 is coupled to theholder 106 to define a reservoir or manifold 180 therebetween (see FIGS.14, 15, 17 and 22). Particularly, when the microneedle array 107 iscoupled to the holder 106, the second side 118 of the microneedle array107, or a portion thereof, can be spaced a distance from the first side(or base) 121 of the holder 106 to define the reservoir 180. As shown inFIGS. 14 and 15, the reservoir 180 can be configured to be closed on allsides to inhibit leakage. Additional sealing members can be employed asnecessary. The fluid path 123 can include or be in fluid communicationwith the reservoir 180, and the reservoir 180 can be in fluidcommunication with the hollow microneedles 108 (i.e., via the secondside 118 of the microneedle array 107). That is, in some embodiments,the substrate 109 can include one or more channels positioned to extendthereacross to provide fluid communication between the first side 116and the second side 118 of the microneedle array 107. As a result, asthe active agent is driven out of the reservoir 111 of the cartridge 110and into the fluid path 123, the active agent is moved to the reservoir180 that is positioned to deliver or feed the active agent to theplurality of hollow microneedles 108, to in turn deliver the activeagent to the skin 50 via the microneedles 108. Other configurations ofproviding fluid communication between the piercing element 175 (e.g.,the rest of the fluid path 123) and the microneedles 108 are possible,and the reservoir 180 is shown by way of example only.

FIGS. 7, 9, 11, 13, 16, 17, and 19-21 illustrate a sterility seal 182positioned to enclose and maintain the sterility of the piercing element175 prior to piercing the septum 177 and positioning the piercingelement 175 in fluid communication with the reservoir 111 of thecartridge 110. Particularly, FIGS. 19-21 show close-up sidecross-sectional views of the piercing element 175 and the sterility seal182, and particularly, show close-up views of the piercing element 175and the sterility seal 182 of FIGS. 9, 11 and 17, respectively, beforethe seal 182 is punctured, as the seal 182 is punctured, and after theseal 182 is punctured and collapsed.

As the shuttle 125 moves the cartridge 110 to the second position S₂,the septum 177 that is positioned over the open end 151 of the cartridge110 contacts and deforms the seal 182 until the piercing element 175pierces or punctures the seal 182 (see FIG. 20). As the shuttle 125 (andthe cartridge 110) continues moving, the piercing element 175 continuesmoving through the seal 182 as it punctures the septum 177. That is, theseal 182 can be configured to deform and collapse toward the base 178 ofthe piercing element 175, and can be further configured to remain in acollapsed configuration after being pierced (e.g., incapable ofreturning to its original position or configuration), as shown in FIG.21.

In some embodiments, the seal 182 can be formed of materials similarthose described above with respect to the septum 177 that allow the seal182 to be pierced during use and seal around the piercing element 175with enough force to prevent leakage during pressurization and transferof the active agent from the reservoir 111, or at least until thepiercing element 175 pierces the septum 177 and the septum 177 canprevent leakage. In some embodiments, the seal 182 merely collapsesaround the piercing element 175 and does not seal around the piercingelement 175.

As further shown in FIGS. 19-21, the sterility seal 182 can beconfigured to change from a first state (see FIG. 19) in which thesterility seal 182 defines a chamber (e.g., a sterile chamber) 184configured to house the piercing element 175 to a second state (see FIG.21) in which the sterility seal 182 has been pierced by the piercingelement 175 and is collapsed, particularly, between the septum 177 (orthe cap 176 or the open end 151 of the cartridge 110) and the base 178of the piercing element 175. FIG. 20 illustrates a third state orcondition that is intermediate of that shown in FIGS. 19 and 21, inwhich the seal 182 is punctured by the piercing element 175.

As mentioned above, the piston 148 and the plunger 149 can be movabletogether between a first, non-dispensing, position (e.g., as shown inFIG. 17) and a second, dispensed, position (e.g., as shown in FIG. 22),respectively. FIGS. 22 and 23 illustrate the apparatus 100 with thepiston 148 and the plunger 149 in their respective second positions.That is, after fluid communication is established (see FIG. 17) betweenthe fluid path 123 and the reservoir 111 of the cartridge 110, theshuttle 125 is maintained in its second position S₂, and the thirdstored energy device 146 continues to drive the indicator 126 in thehousing 102, e.g., along the longitudinal axis L, which also drives theplunger 149, which in turns moves the piston 148 within the cartridge110 to force the active agent into the fluid path 123. FIG. 23illustrates what a user would see when infusion or delivery of theactive agent is complete and the apparatus 100 can be removed from theskin 50.

In use, the cover 113 and release liner 152 can be removed. Theskin-contact adhesive 150 on the base 133 of the actuator 104 (and/or onthe base 112 of the housing 102) can be applied to the skin 50. An upperportion (e.g., the first portion 120) of the housing 102 of theapparatus 100 can be pressed toward the skin 50 to cause the actuator104 to move from its first position P₁ (as shown in FIGS. 7 and 8, whichillustrate a first condition of the apparatus 100) to its secondposition P₂ (as shown in FIGS. 9 and 10, which illustrate a secondcondition of the apparatus 100), e.g., against the bias of the biasingelement 128.

Movement of the actuator 104 to its second position P₂ releases theshuttle 125 (i.e., by moving the shuttle stop 154) to allow the shuttle125 to begin moving toward its second position S₂ (as shown in FIGS. 11and 12, which illustrate a third condition of the apparatus 100), e.g.,as a result of being driven by the second stored energy device 144 (asshown in FIG. 11). After the shuttle 125 is moved to a third position S₃located between its first and second positions S₁ and S₂, the holderstop 160 on the shuttle 125 is no longer positioned to retain themicroneedle array holder 106 in its retracted position H₁, such that theholder 106 is released, and the first stored energy device 138 can beginto provide forces to drive the microneedle array holder 106 toward itsextended position H₂ (as shown in FIGS. 13-14, which illustrate a fourthcondition of the apparatus 100). In the illustrated embodiment, FIGS. 13and 14 show a dampened position of the holder 106, and the holder 106can continue to its full extended position H₂ (and accordingly, themicroneedle array 107 can continue to its extended position M₂), asshown in FIGS. 15 and 16, which illustrate a fifth condition of theapparatus 100. However, some embodiments do not employ the dampener 163or the dampened position of the holder 106 illustrated in FIGS. 13 and14. The shuttle 125 then continues to move toward its second position S₂and the first indicator portion 126 a and the second indicator portion126 b are allowed to separate (as shown in FIG. 16), at which point thethird stored energy device 146 can provide, or assist in providing,forces to continue to move the shuttle 125 to the second position S₂.

When the shuttle 125 reaches its second position S₂ (as shown in FIG.17, which illustrates a sixth condition of the apparatus 100), thereservoir 111 of the cartridge 110 of the infusion assembly 103 isplaced into fluid communication with the fluid path 123, andparticularly with the microneedles 108 in the injection assembly 101.Also, at this point, the indicator 126 (e.g., the first indicatorportion 126 a) can begin to move relative to the shuttle 125, which candrive the piston 148 in the reservoir 111 (e.g., with the plunger 149),and the progress of the piston 148 can be displayed to a user by theindicator 126, which can be visible through the window 124 in thehousing 102 (as shown in FIG. 18). When the piston 148 and the plunger149 (and the indicator 126) reach their respective second positions (asshown in FIGS. 22 and 23, which illustrate a seventh condition of theapparatus 100), infusion of the active agent is complete. This can beindicated to a user with the indicator 126, which can be visible throughthe window 124 of the housing 102, e.g., by showing the indicator 126 asfilling up the window 124.

FIGS. 24 and 25 illustrate the cover 113 in greater detail. As mentionedabove, the cover 113 can include (i) a first (e.g., outer) portion 140configured to cover at least a portion of the base 112 of the housing102 adjacent the opening 115, as well as the base 133 of the actuator104; and (ii) a second (e.g., inner) portion 142 configured to bereceived in the cavity 114 of the housing 112 and further configured tocover the plurality of microneedles 108 on the microneedle array 107when the microneedle array holder 106 is in the retracted position H₁.The second portion 142 can also be configured to be received in thecavity 134 of the actuator 104, e.g., in embodiments employing aninverted actuator 104 through which the microneedle array 107 isdeployed. In addition, the first portion 140 can cover the base 133 ofthe actuator 104 adjacent the opening 135 in embodiments employing aninverted actuator 104 through which the microneedle array 107 isdeployed.

As mentioned above, the base 133 of the actuator 104 and/or the base 112of the housing 102 can include the skin-contact adhesive 150 and anyoptional release liners 152. In such embodiments, the cover 113 (i.e.,the first portion 140 thereof) can be configured to cover at least theportion of the base 133 (and/or the base 112) including the skin-contactadhesive 150 and, optionally, any release liners 152 employed,particularly when the actuator 104 is in the first position P₁. However,in some embodiments, after the apparatus 100 has been used and removedfrom the skin 50, the cover 113 can be used to re-cover the actuator 104and the base 112 of the housing 102, with the actuator 104 in its secondposition P₂.

In the illustrated embodiment, the first portion 140 and the secondportion 142 of the cover 113 are integrally formed together. However, insome embodiments, the first and second portions 140 and 142 can beremovably coupled together, which can allow the base 133 (and/or thebase 112) to be covered and/or uncovered independently of themicroneedles 108.

By way of example only, the second portion 142 is illustrated as beinggenerally tubular in shape, such that the second portion 142 can extendthrough the opening 135 (and/or the opening 115) in the base 133 (and/orthe base 112) and into the cavity 134 of the actuator 104 (and/or thecavity 114 of the housing 112).

As shown in FIG. 25, the first portion 140 can include or define arecess (or chamber or pocket) 195 (i.e., with a closed end 197)dimensioned to receive at least a portion of the base 133 of theactuator 104 and/or at least a portion of the base 112 of the housing102. In embodiments in which the cover 113 covers the actuator 104, theclosed end or base 197 of the recess 195 can be spaced a distance fromthe base 133 of the actuator 104 when the cover 113 is coupled to theapparatus 100, such that the actuator 104 is not undesirably orprematurely actuated 104 prior to use.

As further shown, the second portion 142 can include or define a recess(or chamber or pocket) 196 (i.e., with a closed end 198) dimensioned toreceive the plurality of microneedles 108 protruding from the firstmajor surface of the first side 116 of the microneedle array 107. Therecess 196 (e.g., the closed end 198) in the second portion 142 can beat least partially defined by an inner surface, and the inner surface ofthe recess 196 and the first side 116 of the microneedle array 107 cantogether define a sterile chamber for housing the plurality ofmicroneedles 108 after assembly of the apparatus 100 and prior to use.Such a sterile chamber can allow sterilizing agent(s) free access to theenclosed volume, while keeping contaminants from entering the chamberpost-sterilization.

As further shown in FIG. 25, in some embodiments, the second portion 142of the cover 113 can include at least one of a projection and a recess,and the first side 116 of the microneedle array 107 (and/or the firstside 121 of the holder 106) can include at least one of a recess and aprojection, respectively, dimensioned to receive the projection and/orproject into the recess of the second portion 142 of the cover 113. Suchan arrangement can allow the second portion 142 to matingly engage withthe microneedle array 107 (and/or the holder 106) and to facilitatehousing and protecting the microneedle array 107 with the second portion142 of the cover 113.

As shown in FIGS. 3 and 25, in the illustrated embodiment, amicroneedle-facing (e.g., an upwardly-facing) recess 199 is illustratedin the second portion 142 of the cover 113 by way of example. As shown,the first side 116 of the microneedle array 107 can include acover-facing (e.g., a downwardly-facing) recess 139 that surrounds theplurality of microneedles 108. As shown in FIGS. 3, 4 and 6, a sealingmember 136 can be employed that is dimensioned to be received in therecess 199 in the second portion 142 of the cover 113 and the recess 139in the microneedle array 107 to seal or close the chamber configured tohouse the microneedles 108 and to provide additional spacing between theclosed end 198 of the recess 196 of the second portion 142 of the cover113 and the first side 116 of the microneedle array 107. This specificarrangement is shown by way of example only, but generally, the secondportion 142 of the cover 113 can be configured to be coupled in some wayto the first side 116 of the microneedle array 107 (and/or the holder106) to enclose and protect the plurality of microneedles 108 prior touse, i.e., to maintain the sterility of the microneedles 108. In someembodiments, the sealing member 136 and/or a portion of the cover 113can be permeable to sterilizing agent(s)) while inhibiting contaminantsfrom entering the chamber after sterilization. In some embodiments, thesecond portion 142 can include or provide the sealing member 136. Insuch embodiments, the sealing member 136 may be integrally formed withthe cover 113 and configured to be coupled to at least one of the firstside 116 of the microneedle array 107 and the first side 121 of themicroneedle array holder 106.

As mentioned above, the housing 102 can include a protrusion 119 thatdefines or includes the base 112. The actuator 104 (e.g., the outerportion 132 thereof) can extend outwardly (e.g., downwardly) from theprotrusion, e.g., when the actuator 104 is in its first position P₁. Therecess 195 in the first portion 140 of the cover 113 can be dimensionedto receive the protrusion of the housing 119 and/or at least a portionof the outer portion 132 of the actuator 104.

The cover 113 can be configured to be coupled to the housing 102 (e.g.,the protrusion 119) and/or the actuator 104 by any of the coupling meansdescribed above. The cover 113 can also be configured to abut a portionof the housing 102 from which the protrusion 119 projects, which canfacilitate inhibiting the cover 113 from pressing the actuator 104 whenthe cover 113 is coupled to the apparatus 100 to prevent prematureactuation of the actuator 104.

While the embodiment of FIGS. 1-25 employs a specific configuration andarrangement of elements and stored energy devices to accomplishinjection and infusion, it should be understood that variations to thespecific structures and arrangements shown in the illustrated embodimentare within the spirit and scope of the present disclosure.

For example, FIG. 26 illustrates an apparatus 100′ according to anotherembodiment of the present disclosure, and particularly, a portion of aninfusion assembly 103′ according to another embodiment of the presentdisclosure. In some embodiments, as shown in FIG. 26, the third storedenergy device 146′ can be configured to directly (rather thanindirectly) engage the plunger 149′ and/or the piston 148′, and theindicator 126′ (e.g., the outer portion 187′ thereof) can still includean outer recess 190′ configured to receive at least a portion of theshuttle 125′ and can ride along the outer surface of the shuttle 125′between the shuttle 125′ and one or more retaining walls 105′ of thehousing 102′ in order to be visible through a window of the housing 102′to indicate the progression of infusion.

For example, in such embodiments, the third stored energy device 146′can be located within the internal chamber 171′ of the inner portion185′ of the indicator 126′ that defines the plunger 149′ (i.e., asopposed to being located between an outer surface of the shuttle 125 andthe outer portion 187′ of the indicator 126). A front end or wall of theplunger 149′ can still contact the piston 148′. Furthermore, in suchembodiments, the second stored energy device 144′ can still initiate themovement of the shuttle 125′ as well as the decoupling of first andsecond indicator portions 125 a′ and 125 b′. Similar to the apparatus100 of FIGS. 1-25, in the apparatus 100′, the first indicator portion126 a′ is located between the shuttle 125′ and the second indicatorportion 126 b′ (and provides coupling therebetween). Still further, theindicator 126′ (or a portion thereof, particularly, the first indicatorportion 126 a′) can travel with the shuttle 125′ until the shuttle 125′reaches its second position, after which, the outer portion 187′ canreach a longitudinal location along longitudinal axis L′ that is beyonda retaining wall 193, allowing the walls forming the outer portion 187′of the indicator 126′ to flex outwardly. At that point, the third storedenergy device 146′ can provide forces to overcome a latch or detent 194coupling the indicator 126′ (i.e., the first indicator portion 126 a′)and the shuttle 125′, allowing the indicator 126′ to begin to move alongthe longitudinal axis L′, relative to the shuttle 125′, allowing theshuttle 125′ to ride inside the outer portion 187′ (i.e., in the outerrecess 190′) to drive the piston 148′ in the cartridge 110′ to infuse anactive agent.

Each embodiment shown in the figures is illustrated as a separateembodiment for clarity in illustrating a variety of features of theapparatuses of the present disclosure. However, it should be understoodthat any combination of elements and features of any of the embodimentsillustrated in the figures and described herein can be employed in theapparatuses of the present disclosure.

The following descriptions of the application time, microneedles,skin-contact adhesive, release liners, and active agents can apply toany embodiment of the apparatuses of the present disclosure.

In some embodiments, the length of time that apparatuses of the presentdisclosure can remain on the skin 50 may be an extended time, however,apparatuses of the present disclosure are more likely to remain on theskin 50 for shorter durations of time. For example, in some embodiments,apparatuses of the present disclosure can remain on the skin for atreatment period of at least 1 second, in some embodiments, at least 5seconds, in some embodiments, at least 10 seconds, in some embodiments,at least 15 seconds, and in some embodiments, at least 30 seconds. Insome embodiments, the apparatus can remain on the skin for a period oftime of no greater than 1 hour, in some embodiments, no greater than 30minutes, in some embodiments, no greater than 20 minutes, in someembodiments, no greater than 10 minutes, and in some embodiments, nogreater than 5 minutes. In some embodiments, the apparatuses can remainon the skin for a treatment period of from 1 second to 1 hour, in someembodiments, from 10 seconds to 10 minutes, and in some embodiments,from 30 seconds to 5 minutes.

In some embodiments, the apparatus 100 can be configured to deliver anactive agent over an infusion period of at least 1 second, in someembodiments, at least 5 seconds, in some embodiments, at least 10seconds, in some embodiments, at least 15 seconds, and in someembodiments, at least 30 seconds. In some embodiments, apparatuses ofthe present disclosure can include infusion periods of no greater thanno greater than 1 hour, in some embodiments, no greater than 30 minutes,in some embodiments, no greater than 20 minutes, in some embodiments, nogreater than 10 minutes, and in some embodiments, no greater than 5minutes. In some embodiments, the apparatuses can remain on the skin fora treatment period of from 1 second to 1 hour, in some embodiments, from10 seconds to 10 minutes, and in some embodiments, from 30 seconds to 5minutes.

Skin-Contact Adhesive

In some embodiments, the skin-contact adhesive 150 can cover the entirebase 133 of the actuator 104 (and/or the base 112 of the housing 102).Alternatively, in some embodiments, the skin-contact adhesive 150 canpartially cover the base 133 (and/or the base 112), e.g., includingintermittent application of the skin-contact adhesive 150 to create gaps(e.g., randomly, or in a pattern), and/or a complete ring ofskin-contact adhesive 150 that has a width that is less than the widthof the base 133 (and/or the base 112).

The skin-contact adhesive 150 is generally a pressure-sensitiveadhesive, and particularly is a pressure-sensitive adhesive that iscapable of securely but releasably adhering or bonding to skin (e.g.,mammalian skin). The skin-contact adhesive 150 is also generally safeand non-toxic. Skin-contact adhesive layers will generally be selectedaccording to the desired end use of the apparatus 100. In someembodiments, the apparatus 100 can include more than one skin-contactadhesive 150. Where the apparatus 100 comprises more than oneskin-contact adhesive layer 150, each skin-contact adhesive layer 150may be selected independently of each other with regard to material andthickness used. Examples of suitable adhesives include acrylates,silicones, polyisobutylenes, synthetic rubber, natural rubber, andcopolymers and mixtures thereof. Acrylates and silicones can bepreferred skin-contact adhesives 150. In general, the skin-contactadhesive 150 should cause little or no irritation or sensitization ofthe skin during the intended wear period.

In some embodiments, the skin-contact adhesive 150 can be an acrylate(or methacrylate) copolymer. Acrylates will typically have an inherentviscosity greater than about 0.2 dL/g and will comprise one or morepolymerized primary monomers and optionally one or more polarcomonomers. Primary monomers suitable for use include alkyl acrylatescontaining 4 to 12 carbon atoms in the alkyl group and alkylmethacrylates containing 4 to 12 carbon atoms in the alkyl group.Examples of suitable alkyl acrylates and methacrylates include n-butyl,n-pentyl, n-hexyl, isoheptyl, n-nonyl, n-decyl, isohexyl, 2-ethyloctyl,isooctyl and 2-ethylhexyl acrylates and methacrylates. In someembodiments, the alkyl acrylates can include isooctyl acrylate,2-ethylhexyl acrylate, n-butyl acrylate, and cyclohexyl acrylate. Polarmonomers suitable for use can include those having hydroxyl, amide, orcarboxylic, sulfonic, or phosphonic acid functionality. Representativeexamples include acrylamide, methacrylamide, N-vinyl-2-pyrrolidone,2-hydroxyethylacrylate, 2-hydroxyethylmethacrylate,hydroxypropylacrylate, acrylic acid, methacrylic acid, pyrrolidonylethyl acrylate, and alkoxyethyl acrylates, such as2-carboxyethylacrylate. In some embodiments, the amount by weight ofpolar monomer will not exceed about 40% of the total weight of allmonomers in order to avoid excessive firmness of the final PSA product.Typically, polar monomers can be incorporated to the extent of about 1%to about 20% by weight. In some embodiments, the polar monomer can beacrylamide.

In some embodiments, the acrylate copolymer can comprise the reactionproduct of primary and polar monomers and additional optional monomerswhich, when present, are included in the polymerization reaction inquantities that will not render the adhesive composition non-tacky. Theoptional additional monomers may be added, for example, to improveperformance, reduce cost, or for other purposes. Examples of suchoptional monomers include vinyl esters, such as vinyl acetate, vinylchloride, vinylidene chloride, styrene, and macromonomerscopolymerizable with the other monomers. Suitable macromonomers includepolymethylmethacrylate, styrene/acrylonitrile copolymer, polyether, andpolystyrene macromonomers. Examples of useful macromonomers and theirpreparation are described in U.S. Pat. No. 4,693,776 (Krampe et al.),the disclosure of which is incorporated herein by reference.

Silicone or polysiloxane pressure-sensitive adhesives includepressure-sensitive adhesives which are based on two major components: apolymer, or gum, and a tackifying resin. The polysiloxane adhesive canbe prepared by cross-linking the gum, typically a high molecular weightpolydiorganosiloxane, with the resin, to produce a three-dimensionalsilicate structure, via a condensation reaction in an appropriateorganic solvent. The ratio of resin to polymer can be adjusted in orderto modify the physical properties of polysiloxane adhesives. Use ofcapped (or amine-compatible) polysiloxanes can, in some embodiments, bepreferred so as to increase drug stability and reduce degradation.Further details and examples of silicone pressure-sensitive adhesiveswhich can be useful are described in the U.S. Pat. No. 4,591,622(Blizzard et al.); U.S. Pat. No. 4,584,355 (Blizzard et al.); U.S. Pat.No. 4,585,836 (Homan et al.); and U.S. Pat. No. 4,655,767 (Woodard etal.). Suitable silicone pressure-sensitive adhesives are commerciallyavailable and include the silicone adhesives sold under the trademarksBIO-PSA® by Dow Corning Corporation, Medical Products, Midland, Mich.

Further description of suitable adhesives may be found in U.S. Pat. No.5,656,286 (Miranda et al.), U.S. Pat. No. 5,223,261 (Nelson et al.), andU.S. Pat. No. 5,380,760 (Wendel et al.), the disclosures of which areincorporated herein by reference. In some embodiments, the thickness ofthe skin-contact adhesive 150 can be at least about 10 μm, in someembodiments, at least about 20 μm, and in some embodiments, at leastabout 40 μm. In some embodiments, the thickness of the skin-contactadhesive 150 can be less than about 2 mm (0.07874 inch), in someembodiments, less than about 1 mm (0.03937 inch), and in someembodiments, less than about 150 microns (5906 microinches).

In some embodiments, a medical grade adhesive can be preferred for theskin-contact adhesive 150. Such a medical grade skin-contact adhesive150 is can have physical properties and characteristics to be capable ofmaintaining intimate contact with the skin 50 before, during, and afteractuation of the apparatus 100. Securing the actuator 104 (or thehousing 102) to the skin 50 can aid in keeping the microneedles 108inserted into the skin 50.

Release Liners

Release liners, which can be used as at least a portion the releaseliner 152 (in addition to other release liners that are employed, e.g.,to cover at least a portion of the base 112), are available from avariety of manufacturers in a wide variety of proprietary formulations.Those skilled in the art will normally test those liners in simulateduse conditions against an adhesive of choice to arrive at a product withthe desired release characteristics. Liners which can be suitable foruse in apparatuses of the present disclosure can be made of kraftpapers, polyethylene, polypropylene, polyester or composites of any ofthese materials. The liner material can be coated with release agents orlow adhesion coatings, such as fluorochemicals or silicones. Forexample, U.S. Pat. No. 4,472,480 (Olson), the disclosure of which ishereby incorporated by reference, describes low surface energyperfluorochemical liners. The liners can be papers, polyolefin films, orpolyester films coated with silicone release materials. Examples ofcommercially available silicone coated release papers are POLYSLIK®silicone release papers available from Loparex (Willowbrook, Ill.).

Active Agent

As mentioned above, in some embodiments, active ingredients or agents(e.g., drugs) can be delivered via the hollow microneedles 108. Anysubstance that can be formulated in a fluid and delivered via hypodermicinjection may be used as the active agent, including any pharmaceutical,nutraceutical, cosmeceutical, diagnostic, and therapeutic agents(collectively referred to herein as “drug” for convenience). The presentdescription envisions that even a gaseous fluid may be utilized.

Examples of drugs that can be incorporated into the apparatuses of thepresent disclosure are those capable of local or systemic effect whenadministered to the skin. Some examples include buprenorphine,clonidine, diclofenac, estradiol, granisetron, isosorbide dinitrate,levonorgestrel, lidocaine, methylphenidate, nicotine, nitroglycerine,oxybutynin, rivastigmine, rotigotine, scopolamine, selegiline,testosterone, tulobuterol, and fentanyl, which are commerciallyavailable in the form of transdermal devices. Other examples includeantiinflammatory drugs, both steroidal (e.g., hydrocortisone,prednisolone, triamcinolone) and nonsteroidal (e.g., naproxen,piroxicam); bacteriostatic agents (e.g., chlorhexidine,hexylresorcinol); antibacterials (e.g., penicillins such as penicillinV, cephalosporins such as cephalexin, erythromycin, tetracycline,gentamycin, sulfathiazole, nitrofurantoin, and quinolones such asnorfloxacin, flumequine, and ibafloxacin); antiprotazoals (e.g.,metronidazole); antifungals (e.g., nystatin); coronary vasodilators;calcium channel blockers (e.g., nifedipine, diltiazem); bronchodilators(e.g., theophylline, pirbuterol, salmeterol, isoproterenol); enzymeinhibitors such as collagenase inhibitors, protease inhibitors,acetylcholinesterase inhibitors (e.g., donepezil), elastase inhibitors,lipoxygenase inhibitors (e.g., A64077), and angiotensin convertingenzyme inhibitors (e.g., captopril, lisinopril); other antihypertensives(e.g., propranolol); leukotriene antagonists (e.g., ICI204,219);anti-ulceratives such as H₂ antagonists; steroidal hormones (e.g.,progesterone); antivirals and/or immunomodulators (e.g.,1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine,1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine,N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide,and acyclovir); local anesthetics (e.g., benzocaine, propofol,tetracaine, prilocaine); cardiotonics (e.g., digitalis, digoxin);antitussives (e.g., codeine, dextromethorphan); antihistamines (e.g.,diphenhydramine, chlorpheniramine, terfenadine); narcotic analgesics(e.g., morphine, fentanyl citrate, sufentanil, hydromorphonehydrochloride); peptide hormones (e.g., human or animal growth hormones,LHRH, parathyroid hormones); cardioactive products such asatriopeptides; antidiabetic agents (e.g., insulin, exanatide); enzymes(e.g., anti-plaque enzymes, lysozyme, dextranase); antinauseants;anticonvulsants (e.g., carbamazine); immunosuppressives (e.g.,cyclosporine); psychotherapeutics (e.g., diazepam); sedatives (e.g.,phenobarbital); anticoagulants (e.g., heparin, enoxaparin sodium);analgesics (e.g., acetaminophen); antimigraine agents (e.g., ergotamine,melatonin, sumatriptan, zolmitriptan); antiarrhythmic agents (e.g.,flecainide); antiemetics (e.g., metaclopromide, ondansetron, granisetronhydrochloride); anticancer agents (e.g., methotrexate); neurologicagents such as anxiolytic drugs; hemostatics; anti-obesity agents;dopamine agonists (e.g., apomorphine); GnRH agonists (e.g., leuprolide,goserelin, nafarelin); fertility hormones (e.g., hCG, hMG,urofollitropin); interferons (e.g., interferon-alpha, interferon-beta,interferon-gamma, pegylated interferon-alpha); and the like, as well aspharmaceutically acceptable salts and esters thereof. The amount of drugthat constitutes a therapeutically effective amount can be readilydetermined by those skilled in the art with due consideration of theparticular drug, the particular carrier, and the desired therapeuticeffect.

In some embodiments, peptide therapeutic agents (natural, synthetic, orrecombinant) can be delivered via the hollow microneedles 108. Examplesof peptide therapeutic agents that can be incorporated into theapparatuses of the present disclosure include parathyroid hormone (PTH),parathyroid hormone related protein (PTHrP), calcitonin, lysozyme,insulin, insulinotropic analogs, glatiramer acetate, goserelin acetate,somatostatin, octreotide, leuprolide, vasopressin, desmopressin,thymosin alpha-1, atrial natriuretic peptide (ANP), endorphin, vascularendothelial growth factor (VEGF), fibroblast-growth factor (FGF),erythropoietin (EPO), bone morphogenetic proteins (BMPs), epidermalgrowth factor (EFG), granulocyte colony-stimulating factor (G-CSF),granulocyte macrophage colony stimulating factor (GM-CSF), insulin-likegrowth factor (IGF), platelet-derived growth factor (PDGF), growthhormone release hormone (GHRH), dornase alfa, tissue plasminogenactivator (tPA), urokinase, ANP clearance inhibitors, lutenizing hormonereleasing hormone (LHRH), melanocyte stimulating hormones (alpha & betaMSH), pituitary hormones (hGH), adrenocorticotropic hormone (ACTH),human chorionic gonadotropin (hCG), streptokinase, interleukins (e.g.IL-2, IL-4, IL-10, IL-12, IL-15, IL-18), protein C, protein S,angiotensin, angiogenin, endothelins, pentigetide, brain natriureticpeptide (BNP), neuropeptide Y, islet amyloid polypeptide (IAPP),vasoactive intestinal peptide (VIP), hirudin, glucagon, oxytocin, andderivatives of any of the foregoing peptide therapeutic agents.

In some embodiments, drugs that are of a large molecular weight may bedelivered transdermally. Increasing molecular weight of a drug typicallycan cause a decrease in unassisted transdermal delivery. Examples ofsuch large molecules include proteins, peptides, nucleotide sequences,monoclonal antibodies, vaccines, polysaccharides, such as heparin, andantibiotics, such as ceftriaxone. Examples of suitable vaccines includetherapeutic cancer vaccines, anthrax vaccine, flu vaccine, Lyme diseasevaccine, rabies vaccine, measles vaccine, mumps vaccine, chicken poxvaccine, small pox vaccine, hepatitis vaccine, hepatitis A vaccine,hepatitis B vaccine, hepatitis C vaccine, pertussis vaccine, rubellavaccine, diphtheria vaccine, encephalitis vaccine, Japanese encephalitisvaccine, respiratory syncytial virus vaccine, yellow fever vaccine,recombinant protein vaccine, DNA vaccines, polio vaccine, therapeuticcancer vaccine, herpes vaccine, human papilloma virus vaccine,pneumococcal vaccine, meningitis vaccine, whooping cough vaccine,tetanus vaccine, typhoid fever vaccine, cholera vaccine, tuberculosisvaccine, severe acute respiratory syndrome (SARS) vaccine, HSV-1vaccine, HSV-2 vaccine, HIV vaccine and combinations thereof. The term“vaccine” thus includes, without limitation, antigens in the forms ofproteins, polysaccharides, oligosaccharides, or weakened or killedviruses. Additional examples of suitable vaccines and vaccine adjuvantsare described in U.S. Patent Application Publication No. 2004/0049150(Dalton et al.), the disclosure of which is hereby incorporated byreference.

In another embodiment, small-molecule drugs that are otherwise difficultor impossible to deliver by passive transdermal delivery may be used.Examples of such molecules include salt forms; ionic molecules, such asbisphosphonates, including sodium alendronate or pamedronate; andmolecules with physicochemical properties that are not conducive topassive transdermal delivery.

Microneedles

Microneedle arrays useful for practicing the present disclosure can havea variety of configurations and features, such as those described in thefollowing patents and patent applications, the disclosures of which areincorporated herein by reference. One embodiment for the microneedlearrays includes the structures disclosed in U.S. Patent ApplicationPublication No. 2005/0261631 (Clarke et al.), which describesmicroneedles having a truncated tapered shape and a controlled aspectratio. Another embodiment for the microneedle arrays includes thestructures disclosed in U.S. Pat. No. 6,091,975 (Daddona et al.), whichdescribes blade-like microprotrusions for piercing the skin. Stillanother embodiment for the microneedle arrays includes the structuresdisclosed in U.S. Pat. No. 6,312,612 (Sherman et al.), which describestapered structures having a hollow central channel Yet still anotherembodiment for the microneedle arrays includes the structures disclosedin U.S. Pat. No. 6,379,324 (Gartstein et al.), which describes hollowmicroneedles having at least one longitudinal blade at the top surfaceof the tip of the microneedle. A further embodiment for the microneedlearrays includes the structures disclosed in U.S. Patent ApplicationPublication Nos. US2012/0123387 (Gonzalez et al.) and US2011/0213335(Burton et al.), which both describe hollow microneedles. A stillfurther embodiment for the microneedle arrays includes the structuresdisclosed in U.S. Pat. No. 6,558,361 (Yeshurun) and U.S. Pat. No.7,648,484 (Yeshurun et al.), which both describe hollow microneedlearrays and methods of manufacturing thereof.

Various embodiments of microneedles that can be employed in themicroneedle arrays of the present disclosure are described in PCTPublication No. WO 2012/074576 (Duan et al.), which describes liquidcrystalline polymer (LCP) microneedles; and PCT Publication No. WO2012/122162 (Zhang et al.), which describes a variety of different typesand compositions of microneedles that can be employed in themicroneedles of the present disclosure.

In some embodiments, the microneedle material can be (or include)silicon, glass, or a metal such as stainless steel, titanium, or nickeltitanium alloy. In some embodiments, the microneedle material can be (orinclude) a polymeric material, such as a medical grade polymericmaterial. Exemplary types of medical grade polymeric materials includepolycarbonate, liquid crystalline polymer (LCP), polyether ether ketone(PEEK), cyclic olefin copolymer (COC), polybutylene terephthalate (PBT).Particularly useful types of medical grade polymeric materials includepolycarbonate and LCP.

In some embodiments, the microneedle material can be (or include) abiodegradable polymeric material, particularly, a medical gradebiodegradable polymeric material. Exemplary types of medical gradebiodegradable materials include polylactic acid (PLA), polyglycolic acid(PGA), PGA and PLA copolymer, polyester-amide polymer (PEA).

In some embodiments, the microneedles can be a prepared from adissolvable, degradable, or disintegradable material referred to hereinas “dissolvable microneedles”. A dissolvable, degradable, ordisintegradable material is any solid material that dissolves, degrades,or disintegrates during use. In particular, a “dissolvable microneedle”dissolves, degrades, or disintegrates sufficiently in the tissueunderlying the stratum corneum to allow a therapeutic agent to bereleased into the tissue. The therapeutic agent may be coated on orincorporated into a dissolvable microneedle. In some embodiments, thedissolvable material is selected from a carbohydrate or a sugar. In someembodiments, the dissolvable material is polyvinyl pyrrolidone (PVP). Insome embodiments, the dissolvable material is selected from the groupconsisting of hyaluronic acid, carboxymethylcellulose,hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol,sucrose, glucose, dextran, trehalose, maltodextrin, and a combinationthereof.

In some embodiments, the microneedles can be made from (or include) acombination of two or more of any of the above mentioned materials. Forexample, the tip of a microneedle may be a dissolvable material, whilethe remainder of the microneedle is a medical grade polymeric material.

A microneedle or the plurality of microneedles in a microneedle arrayuseful for practicing the present disclosure can have a variety ofshapes that are capable of piercing the stratum corneum. In someembodiments, one or more of the plurality of microneedles can have asquare pyramidal shape, triangular pyramidal shape, stepped pyramidalshape, conical shape, microblade shape, or the shape of a hypodermicneedle. In some embodiments, one or more of the plurality ofmicroneedles can have a square pyramidal shape. In some embodiments, oneor more of the plurality of microneedles can have a triangular pyramidalshape. In some embodiments, one or more of the plurality of microneedlescan have a stepped pyramidal shape. In some embodiments, one or more ofthe plurality of microneedles can have a conical shape. In someembodiments, one or more of the plurality of microneedles can have amicroblade shape. In some embodiments, one or more of the plurality ofmicroneedles can have the shape of a hypodermic needle. The shape can besymmetric or asymmetric. The shape can be truncated (for example, theplurality of microneedles can have a truncated pyramid shape ortruncated cone shape). The plurality of microneedles in a microneedlearray are preferably hollow microneedles (that is, the microneedlescontain a hollow bore through the microneedle). The hollow bore can befrom the base of the microneedle to the tip of the microneedle or thebore can be from the base of the microneedle to a position offset fromthe tip of the microneedle. In some embodiments, one or more of theplurality of hollow microneedles in a hollow microneedle array can havea conical shape, cylindrical shape, square pyramidal shape, triangularpyramidal shape, or the shape of a hypodermic needle.

In some embodiments, one or more of the plurality of hollow microneedlesin a hollow microneedle array can have a conical shape. In someembodiments, one or more of the plurality of hollow microneedles in ahollow microneedle array can have a cylindrical shape. In someembodiments, one or more of the plurality of hollow microneedles in ahollow microneedle array can have a square pyramidal shape. In someembodiments, one or more of the plurality of hollow microneedles in ahollow microneedle array can have a triangular pyramidal shape. In someembodiments, one or more of the plurality of hollow microneedles in ahollow microneedle array can have the shape of a hypodermic needle. In apreferred embodiment, the plurality of hollow microneedles in a hollowmicroneedle array each have the shape of a conventional hypodermicneedle.

FIG. 27 shows a portion of the microneedle array 107 that includes fourmicroneedles 108 (of which two are referenced in FIG. 27) positioned ona microneedle substrate 109. Each microneedle 108 has a height h, whichis the length from the tip of the microneedle 108 to the microneedlebase at substrate 109. Either the height of a single microneedle or theaverage height of all microneedles on the microneedle array can bereferred to as the height of the microneedle, h. In some embodiments,each of the plurality of microneedles (or the average of all of theplurality of microneedles) has a height of about 100 to about 3000micrometers, in some embodiments, about 100 to about 1500 micrometers,in some embodiments, about 100 to about 1200 micrometers, and, in someembodiments, about 100 to about 1000 micrometers.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) has a height of about200 to about 1200 micrometers, about 200 to about 1000 micrometers,about 200 to about 750 micrometers, or about 200 to about 600micrometers.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) has a height of about250 to about 1500 micrometers, about 500 to about 1000 micrometers, orabout 500 to about 750 micrometers.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) has a height of about800 to about 1400 micrometers.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) has a height of about500.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) has a height of lessthan about 3000 micrometers. In other embodiments, each of the pluralityof microneedles (or the average of all of the plurality of microneedles)has a height of less than about 1500 micrometers. In still otherembodiments, each of the plurality of microneedles (or the average ofall of the plurality of microneedles) has a height of less than about1200 micrometers. In yet still other embodiments, each of the pluralityof microneedles (or the average of all of the plurality of microneedles)has a height of less than about 1000 micrometers. In furtherembodiments, each of the plurality of microneedles (or the average ofall of the plurality of microneedles) has a height of less than about750 micrometers. In still further embodiments, each of the plurality ofmicroneedles (or the average of all of the plurality of microneedles)has a height of less than about 600 micrometers.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) has a height of atleast about 100 micrometers. In other embodiments, each of the pluralityof microneedles (or the average of all of the plurality of microneedles)has a height of at least about 200 micrometers. In still otherembodiments, each of the plurality of microneedles (or the average ofall of the plurality of microneedles) has a height of at least about 250micrometers. In further embodiments, each of the plurality ofmicroneedles (or the average of all of the plurality of microneedles)has a height of at least about 500 micrometers. In still furtherembodiments, each of the plurality of microneedles (or the average ofall of the plurality of microneedles) has a height of at least about 800micrometers.

In some embodiments employing hollow microneedles, each of the pluralityof hollow microneedles (or the average of all of the plurality of hollowmicroneedles) has a height of about 100 to about 3000 micrometers, about800 to about 1400 micrometers, or about 500 micrometers.

In some embodiments, each of the plurality of hollow microneedles (orthe average of all of the plurality of hollow microneedles) has a heightof about 900 to about 1000 micrometers. In other embodiments, each ofthe plurality of hollow microneedles (or the average of all of theplurality of hollow microneedles) has a height of about 900 to about 950micrometers. In still other embodiments, each of the plurality of hollowmicroneedles (or the average of all of the plurality of hollowmicroneedles) has a height of about 900 micrometers.

A single microneedle or the plurality of microneedles in a microneedlearray can also be characterized by their aspect ratio. The aspect ratioof a microneedle is the ratio of the height of the microneedle, h to thewidth (at the base of the microneedle), w (as shown in FIG. 27). Theaspect ratio can be presented as h:w. In some embodiments, each of theplurality of microneedles (or the average of all the plurality ofmicroneedles) has (have) an aspect ratio in the range of 2:1 to 5:1. Insome of these embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) has (have) an aspectratio of at least 3:1.

In some embodiments, the array of microneedles contains about 100 toabout 1500 microneedles per cm² of the array of microneedles.

In some embodiments employing hollow microneedles, the array of hollowmicroneedles contains about 3 to about 30 hollow microneedles per arrayof hollow microneedles.

In some embodiments, the array of hollow microneedles contains about 10to about 30 hollow microneedles per array of hollow microneedles.

In some embodiments, the array of hollow microneedles contains about 3to about 20 hollow microneedles per array of hollow microneedles.

In some embodiments, the array of hollow microneedles contains about 13to about 20 hollow microneedles per array of hollow microneedles.

In some embodiments, the array of hollow microneedles contains about 8to about 18 hollow microneedles per array of hollow microneedles.

In some embodiments, the array of hollow microneedles contains about 18hollow microneedles per array of hollow microneedles.

In some embodiments, the array of hollow microneedles contains about 12hollow microneedles per array of hollow microneedles.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) in a microneedle arraycan penetrate into the skin to a depth of about 50 to about 1500micrometers, about 50 to about 400 micrometers, or about 50 to about 250micrometers.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) in a microneedle arraycan penetrate into the skin to a depth of about 100 to about 400micrometers, or about 100 to about 300 micrometers.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) in a microneedle arraycan penetrate into the skin to a depth of about 150 to about 1500micrometers, or about 800 to about 1500 micrometers.

In some embodiments, each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) in a microneedle arraycan penetrate into the skin to a depth of about 400 to about 800micrometers.

For all of the above embodiments, it will be appreciated that the depthof penetration (DOP) of each of the plurality of microneedles (or theaverage of all of the plurality of microneedles) in a microneedle arraymay not be the full length of the microneedles themselves.

In some embodiments, the microneedle array 107 according to the presentdisclosure can be in the form of a patch, which can include themicroneedle array 107, a skin-contact adhesive, such as those describedabove, and optionally a backing. Whether on a patch or not, themicroneedles 108 can be arranged in any desired pattern or arrangement.For example, the microneedles 108 can be arranged in uniformly spacedrows, which can be aligned or offset. In some embodiments, themicroneedles 108 can be arranged in a polygonal pattern such as atriangle, square, rectangle, pentagon, hexagon, heptagon, octagon, ortrapezoid. In other embodiments, the microneedles 108 can be arranged ina circular or oval pattern.

In some embodiments, the surface area of the substrate 109 covered withmicroneedles 108, can be about 0.1 cm² to about 20 cm². In some of theseembodiments, the surface area of the substrate 109 covered withmicroneedles 108 is about 0.5 cm² to about 5 cm². In some other of theseembodiments, the surface area of the substrate 109 covered withmicroneedles 108 is about 1 cm² to about 3 cm². In still other of theseembodiments, the surface area of the substrate 109 covered withmicroneedles 108 is about 1 cm² to about 2 cm².

In some embodiments, the microneedles 108 of the present disclosure canbe disposed over substantially the entire surface of the array 107(e.g., of the substrate 109). In other embodiments, a portion of thesubstrate 109 may not be provided with microneedles 108 (that is, aportion of the substrate 109 is non-structured). In some of theseembodiments, the non-structured surface has an area of more than about 1percent and less than about 75 percent of the total area of the devicesurface that faces the skin surface 50. In another of these embodiments,the non-structured surface has an area of more than about 0.65 cm² (0.10square inch) to less than about 6.5 cm² (1 square inch).

For hollow microneedles, a hollow channel or bore extends through thesubstrate 109 and microneedles 108. In some embodiments, the bore exitsat a channel opening at or near the tip of the hollow microneedle. Thechannel preferably exits at an opening near the tip of the hollowmicroneedle. Most preferably, the channel or bore continues along acentral axis of the microneedle, but exits similar to a hypodermicneedle on a sloping side-wall of the microneedle to help preventblockage of the channel by tissue upon insertion. In some embodiments,the diameter of the channel bore is about 10 to about 200 micrometers.In other embodiments, the diameter of the channel bore is about 10 toabout 150 micrometers. In still other embodiments, the diameter of thechannel bore is about 30 to about 60 micrometers.

In some embodiments of hollow microneedles, the average cross-sectionalarea of the channel bore is about 75 to about 32,000 micrometers. Inother embodiments of hollow microneedles, the average cross-sectionalarea of the channel bore is about 75 to about 18,000 micrometers. Instill other embodiments of hollow microneedles, the averagecross-sectional area of the channel bore is about 700 to about 3,000micrometers.

In some embodiments of hollow microneedle arrays, the average spacingbetween adjacent microneedles (as measured from microneedle tip tomicroneedle tip) is between about 0.7 mm and about 20 mm. In otherembodiments of hollow microneedle arrays, the average spacing betweenadjacent microneedles is between about 0.7 mm and about 10 mm. In stillother embodiments of hollow microneedle arrays, the average spacingbetween adjacent microneedles is between about 2 mm and about 20 mm. Instill other embodiments of hollow microneedle arrays, the averagespacing between adjacent microneedles is between about 2 mm and about 10mm. In a preferred embodiment of hollow microneedle arrays, the averagespacing between adjacent microneedles is between about 2 mm.

In some embodiments of hollow microneedle arrays, the average spacingbetween adjacent microneedles (as measured from microneedle tip tomicroneedle tip) is greater than about 0.7 mm. In other embodiments ofhollow microneedle arrays, the average spacing between adjacentmicroneedles is greater than about 2 mm.

In some embodiments of hollow microneedle arrays, the average spacingbetween adjacent microneedles is less than about 20 mm. In otherembodiments of hollow microneedle arrays, the average spacing betweenadjacent microneedles is less than about 10 mm.

The microneedle arrays can be manufactured in any suitable way such asby injection molding, compression molding, metal injection molding,stamping, photolithography, or extrusion. In one embodiment, hollowmicroneedle arrays can be made by thermocycled injection molding of apolymer such as medical grade polycarbonate or LCP, followed by laserdrilling to form the channels of the microneedles.

The following embodiments are intended to be illustrative of the presentdisclosure and not limiting.

Embodiments

1. A microneedle injection and infusion apparatus comprising:

-   -   a housing having a base and a cavity that extends through the        base to define an opening in the base, wherein the base of the        housing is configured to be positioned toward a skin surface;    -   a microneedle array holder configured to hold a microneedle        array and located in the housing, the microneedle array holder        movable with respect to the opening in the base of the housing        between        -   a retracted position in which the microneedle array is            recessed within the housing such that the microneedle array            does not contact the skin surface when the apparatus is            positioned on the skin surface and the microneedle array is            coupled to the microneedle array holder, and        -   extended position in which at least a portion of the            microneedle array is positioned to contact the skin surface            via the opening when the apparatus is positioned on the skin            surface and the microneedle array is coupled to the            microneedle array holder;    -   a shuttle configured to hold and carry a cartridge, the        cartridge defining a reservoir configured to contain an active        agent, the shuttle being movable between a first position in        which the reservoir of the cartridge is not in fluid        communication with a fluid path and a second position in which        the reservoir is in fluid communication with the fluid path; and    -   an actuator movable between a first position and a second        position, wherein movement of the actuator to the second        position releases the shuttle from its first position and allows        the shuttle to move toward its second position, and wherein        movement of the shuttle toward its second position releases the        microneedle array holder from the retracted position and allows        the microneedle array holder to move to the extended position.

2. A method of using a microneedle injection apparatus, the methodcomprising:

-   -   providing a microneedle injection apparatus comprising:        -   a housing having a base and a cavity that extends through            the base to define an opening in the base, wherein the base            of the housing is configured to be positioned toward a skin            surface;        -   a microneedle array holder configured to hold a microneedle            array and located in the housing, the microneedle array            holder movable with respect to the opening in the base of            the housing between            -   a retracted position in which the microneedle array is                recessed within the housing such that the microneedle                array does not contact the skin surface when the                apparatus is positioned on the skin surface and the                microneedle array is coupled to the microneedle array                holder, and            -   an extended position in which at least a portion of the                microneedle array is positioned to contact the skin                surface via the opening when the apparatus is positioned                on the skin surface and the microneedle array is coupled                to the microneedle array holder;        -   a shuttle configured to hold and carry a cartridge, the            cartridge defining a reservoir configured to contain an            active agent, the shuttle being movable between a first            position in which the reservoir is not in fluid            communication with a fluid path and a second position in            which the reservoir is in fluid communication with the fluid            path; and        -   an actuator movable between a first position and a second            position;    -   moving the actuator to its second position to allow the shuttle        to move toward its second position, wherein movement of the        shuttle toward its second position allows the microneedle array        holder to move to its extended position.

3. The method of embodiment 2, wherein the microneedle array holder ismoved to its extended position prior to the shuttle being fully moved toits second position, such that the microneedle array holder is in itsextended position before the shuttle is in its second position.

4. The method of embodiment 2 or 3, further comprising providing a delaybetween moving the microneedle array holder to its extended position andmoving the shuttle to its second position.

5. The method of any of embodiments 2-4, wherein the microneedle arrayholder is moved to its extended position before the shuttle hascompleted movement to its second position.

6. The method of any of embodiments 2-5, wherein the microneedle arrayholder is in its extended position when the shuttle reaches its secondposition.

7. The apparatus of embodiment 1 or the method of any of embodiments2-6, wherein the fluid path includes the microneedle array when themicroneedle array is coupled to the microneedle array holder.

8. The apparatus of embodiment 1 or 7 or the method of any ofembodiments 2-7, wherein the microneedle array includes a plurality ofhollow microneedles, and wherein the fluid path includes the pluralityof hollow microneedles.

9. The apparatus of any of embodiments 1, 7 and 8 or the method of anyof embodiments 2-8, wherein the fluid path is configured to deliver theactive agent to the microneedle array when the microneedle array iscoupled to the microneedle array holder.

10. The apparatus of any of embodiments 1 and 7-9 or the method of anyof embodiments 2-9, wherein the microneedle array includes a pluralityof hollow microneedles, and wherein the fluid path is configured todeliver the active agent to the plurality of hollow microneedles whenthe microneedle array is coupled to the microneedle array holder.

11. The apparatus of any of embodiments 1 and 7-10 or the method of anyof embodiments 2-10, wherein the fluid path is in fluid communicationwith the microneedle array when the microneedle array is coupled to themicroneedle array holder.

12. The apparatus of any of embodiments 1 and 7-11 or the method of anyof embodiments 2-11, wherein the microneedle array includes a pluralityof hollow microneedles, and wherein the fluid path is in fluidcommunication with the plurality of hollow microneedles when themicroneedle array is coupled to the microneedle array holder.

13. The apparatus of any of embodiments 1 and 7-12 or the method of anyof embodiments 2-12, wherein the microneedle array includes a first sidecomprising a first major surface and a plurality of hollow microneedlesthat protrude from the first major surface.

14. The apparatus or method of embodiment 13, wherein the microneedlearray includes a second side opposite the first side, wherein theplurality of hollow microneedles are in fluid communication with thesecond side, and wherein the microneedle array is configured to becoupled to a base of the microneedle array holder such that the secondside of the microneedle array and the base of the microneedle arrayholder are spaced a distance apart to define a manifold for theplurality of hollow microneedles.

15. The apparatus of any of embodiments 1 and 7-14 or the method of anyof embodiments 2-14, wherein the shuttle is biased in the secondposition, and wherein the microneedle array holder is biased in theextended position.

16. The apparatus of any of embodiments 1 and 7-15 or the method of anyof embodiments 2-15, wherein the shuttle is held in its first positionby the actuator when the actuator is in its first position.

17. The apparatus of any of embodiments 1 and 7-16 or the method of anyof embodiments 2-16, wherein the microneedle array holder is held in theretracted position by the shuttle, when the shuttle is in its firstposition.

18. The apparatus of any of embodiments 1 and 7-17 or the method of anyof embodiments 2-17, wherein at least a portion of the shuttle isconfigured to hold the actuator in the second position after theactuator has been moved to the second position.

19. The apparatus of any of embodiments 1 and 7-18 or the method of anyof embodiments 2-18, wherein the actuator is held in its second positionby the shuttle.

20. The apparatus of any of embodiments 1 and 7-19 or the method of anyof embodiments 2-19, wherein the microneedle array holder is movablebetween the retracted position and the extended position along a firstaxis, wherein the shuttle is movable between the first position and thesecond position along a second axis, and wherein the first axis and thesecond axis are oriented at a non-zero angle with respect to oneanother.

21. The apparatus or method of embodiment 20, wherein the first axis andthe second axis are oriented substantially perpendicularly with respectto one another.

22. The apparatus of any of embodiments 1 and 7-21 or the method of anyof embodiments 2-21, wherein the actuator includes a shuttle stopmovable between (i) a first position in which the shuttle stop ispositioned to engage at least a portion of the shuttle to hold theshuttle in the first position, and (ii) a second position in which theshuttle stop is no longer positioned to engage the shuttle to hold theshuttle in the first position, such that when the shuttle stop is in thesecond position, the shuttle is free to move to the second position.

23. The apparatus or method of embodiment 22, wherein the shuttle isbiased in the second position.

24. The apparatus or method of embodiment 22 or 23, further comprising astored energy device configured to drive the shuttle toward the secondposition.

25. The apparatus or method of any of embodiments 22-24, wherein whenthe actuator is in the second position, the shuttle stop is positionedto hold the actuator in the second position.

26. The apparatus or method of any of embodiments 22-25, wherein whenthe actuator is in the second position, the shuttle stop is positionedto engage at least a portion of the shuttle to hold the actuator in thesecond position.

27. The apparatus or method of any of embodiments 22-26, wherein theactuator is held in the second position by an engagement between theshuttle stop and at least a portion of the shuttle.

28. The apparatus of any of embodiments 1 and 7-27 or the method of anyof embodiments 2-27, wherein the shuttle includes a holder stop movablefrom (i) a first position in which the holder stop is positioned toengage with at least a portion of the microneedle array holder to holdthe microneedle array holder in the retracted position to (ii) a secondposition in which the holder stop is no longer positioned to engage withthe microneedle array holder to hold the microneedle array holder in theretracted position, such that when the holder stop is in the secondposition, the microneedle array holder is free to move to the extendedposition.

29. The apparatus or method of embodiment 28, wherein the microneedlearray holder is biased in the extended position.

30. The apparatus or method of embodiment 28 or 29, further comprising astored energy device configured to drive the microneedle array holdertoward the extended position.

31. The apparatus of any of embodiments 1 and 7-30 or the method of anyof embodiments 2-30, wherein at least a portion of the actuator islocated on the base of the housing and is configured to be moved fromthe first position to the second position in response to the apparatusbeing pressed toward the skin surface.

32. The apparatus of any of embodiments 1 and 7-31 or the method of anyof embodiments 2-31, wherein at least a portion of the actuator islocated on a skin-facing portion of the apparatus and is configured tobe moved from the first position to the second position in response tothe apparatus being pressed toward a skin surface by pressing on anon-skin-facing portion of the apparatus.

33. The apparatus or method of embodiment 32, wherein thenon-skin-facing portion of the apparatus is located in an off-axisposition with respect to an actuation axis of the actuator.

34. The apparatus of any of embodiments 1 and 7-33 or the method of anyof embodiments 2-33, wherein at least a portion of the actuator islocated on a lower portion of the housing, and wherein the actuator isconfigured to be moved from the first position to the second position inresponse to the apparatus being pressed toward a skin surface bypressing on an upper portion of the housing.

35. The apparatus or method of embodiment 34, wherein the upper portionof the housing is located in an off-axis position with respect to anactuation axis of the actuator.

36. The apparatus of any of embodiments 1 and 7-35 or the method of anyof embodiments 2-35, wherein the actuator is configured to be moved fromthe first position to the second position when a non-skin-facing portionof the housing is pressed toward a skin surface.

37. The apparatus or method of embodiment 36, wherein thenon-skin-facing portion of the housing is not located directly oppositethe actuator.

38. The apparatus or method of embodiment 36 or 37, wherein thenon-skin-facing portion of the housing is located in an off-axisposition with respect to an actuation axis of the actuator.

39. The apparatus of any of embodiments 1 and 7-38 or the method of anyof embodiments 2-38, wherein the actuator is movable with respect to thebase of the housing, and wherein

-   -   when the actuator is in the first position, an outermost surface        of the actuator extends beyond the base of the housing by a        first distance, and    -   when the actuator is in the second position, the outermost        surface of the actuator        -   does not extend beyond the base of the housing, or        -   extends beyond the base of the housing by a second distance            that is less than the first distance.

40. The apparatus of any of embodiments 1 and 7-39 or the method of anyof embodiments 2-39, wherein the actuator is movable between the firstposition and the second position along a first actuation axis, whereinthe microneedle array holder is movable between the retracted positionand the extended position along a second actuation axis, and wherein thefirst actuation axis and the second actuation axis are substantiallyparallel with respect to one another.

41. The apparatus or method of embodiment 40, wherein at least a portionof the actuator extends beyond the base of the housing when the actuatoris in the first position.

42. The apparatus or method of embodiment 40 or 41, wherein the firstactuation axis and the second actuation axis are substantially aligned.

43. The apparatus or method of any of embodiments 40-42, wherein theshuttle is movable between the first position and the second positionalong a third axis, and wherein the third axis is oriented at a non-zeroangle with respect to at least one of the first axis and the secondaxis.

44. The apparatus or method of any of embodiments 40-43, wherein thethird axis is oriented substantially perpendicularly with respect to atleast one of the first axis and the second axis.

45. The apparatus of any of embodiments 1 and 7-44 or the method of anyof embodiments 2-44, wherein at least a portion of the housing isconfigured to be pressed using any portion of a hand.

46. The apparatus of any of embodiments 1 and 7-45 or the method of anyof embodiments 2-45, wherein at least a portion of the actuator ismovable with respect to the base of the housing into and out of theopening formed in the base of the housing.

47. The apparatus of any of embodiments 1 and 7-46 or the method of anyof embodiments 2-46, wherein at least a portion of the actuator extendsinto the cavity of the housing.

48. The apparatus of any of embodiments 1 and 7-47 or the method of anyof embodiments 2-47, wherein the actuator includes a base and a cavitythat extends through the base of the actuator to form an opening in thebase of the actuator, and wherein the microneedle array holder ismovable in the cavity of the actuator when the microneedle array holderis moved between the retracted position and the extended position.

49. The apparatus or method of embodiment 48, wherein the actuatorincludes a base and an opening formed in the base, and wherein at leasta portion of the microneedle array extends through the opening in theactuator and beyond the base of the actuator when the microneedle arrayholder is in the extended position.

50. The apparatus or method of embodiment 49, wherein the base of theactuator is configured to be coupled to the skin surface.

51. The apparatus or method of embodiment 49 or 50, wherein the base ofthe actuator includes a skin-contact adhesive.

52. The apparatus of any of embodiments 1 and 7-51 or the method of anyof embodiments 2-51, wherein the actuator includes a skin-contactadhesive.

53. The apparatus of any of embodiments 1 and 7-52 or the method of anyof embodiments 2-52, wherein, when the actuator is in the firstposition, at least a portion of the actuator protrudes from the openingin the base of the housing and defines a base configured to be coupledto the skin surface.

54. The apparatus or method of embodiment 53, wherein the first surfaceincludes a skin-contact adhesive.

55. The apparatus of any of embodiments 1 and 7-54 or the method of anyof embodiments 2-54, wherein at least a portion of the actuator islocated in the cavity of the housing and positioned to at leastpartially surround the microneedle array, at least when the microneedlearray holder is in the extended position.

56. The apparatus of any of embodiments 1 and 7-55 or the method of anyof embodiments 2-55, wherein at least a portion of the actuator islocated adjacent the opening in the base of the housing, and wherein atleast a portion of the microneedle array extends beyond the actuatorwhen the microneedle array holder is in the extended position.

57. The apparatus of any of embodiments 1 and 7-56 or the method of anyof embodiments 2-56, wherein the actuator is biased in the firstposition.

58. The apparatus of embodiment any of embodiments 1 and 7-57 or themethod of any of embodiments 2-57, further comprising a biasing elementconfigured to bias the actuator in the first position, wherein theactuator is movable from the first position to the second positionagainst the bias of the biasing element.

59. The apparatus of any of embodiments 1 and 7-58 or the method of anyof embodiments 2-58, wherein the microneedle array holder is biased inthe extended position.

60. The apparatus of any of embodiments 1 and 7-59 or the method of anyof embodiments 2-59, wherein the shuttle is biased toward the secondposition, and wherein the shuttle is restrained from moving to thesecond position by the actuator, until the actuator is moved to thesecond position.

61. The apparatus of any of embodiments 1 and 7-60 or the method of anyof embodiments 2-60, further comprising a stored energy deviceconfigured to drive the shuttle toward the second position.

62. The apparatus or method of embodiment 61, wherein the stored energydevice is one of a plurality of stored energy devices that cooperate todrive the shuttle toward the second position.

63. The apparatus of any of embodiments 1 and 7-62 or the method of anyof embodiments 2-62, further comprising an active agent and a pistonlocated in the reservoir of the cartridge, the piston movable between afirst position in which the active agent is not being forced out of thereservoir and moved into the fluid path and a second position in whichthe active agent is being forced out of the reservoir and moved into thefluid path.

64. The apparatus or method of embodiment 63, further comprising astored energy device configured to drive the shuttle toward the secondposition, wherein the stored energy device is further configured todrive the piston toward its second position.

65. The apparatus or method of embodiment 63 or 64, further comprising afirst stored energy device configured to initiate movement of theshuttle toward the second position and a second stored energy deviceconfigured to assist in moving the shuttle toward the second positionand further configured to drive the piston toward its second position.

66. The apparatus or method of any of embodiments 63-65, wherein thepiston is movable to the second position when the shuttle is in itssecond position.

67. The apparatus or method of any of embodiments 63-66, furthercomprising an indicator that is movable with the piston between thefirst position and the second position of the piston, wherein theindicator is visible from outside the housing to indicate the positionof the piston with respect to the housing.

68. The apparatus or method of embodiment 67, wherein the indicator ismovable with the shuttle from the first position of the shuttle to thesecond position of the shuttle, and wherein the indicator is furthermovable with the piston and with respect to the shuttle when the shuttleis in the second position.

69. The apparatus or method of embodiment 67 or 68, wherein theindicator is formed of at least two portions that are removably coupledtogether.

70. The apparatus or method of any of embodiments 67-69, wherein atleast a portion of the indicator is movable with respect to the shuttlewhen the shuttle is in the second position.

71. The apparatus or method of any of embodiments 67-70, wherein atleast a portion of the indicator is coupled to a plunger that isconfigured to abut the piston.

72. The apparatus or method of embodiment 71, wherein the plunger ispositioned to drive the piston to its second position.

73. The apparatus of any of embodiments 1 and 7-72 or the method of anyof embodiments 2-72, wherein the fluid path includes or is in fluidcommunication with a piercing element configured to provide fluidcommunication between the reservoir of the cartridge and the fluid path,and further comprising a deformable sterility seal positioned to enclosethe piercing element and configured to be pierced by the piercingelement.

74. The apparatus or method of embodiment 73, wherein the sterility sealis further configured to be changed from a first state in which thesterility seal defines a sterile chamber within which the piercingelement is located to a second state in which the sterility seal hasbeen pierced by the piercing element and the sterility seal iscollapsed.

75. The apparatus of any of embodiments 1 and 7-74 or the method of anyof embodiments 2-74, further comprising a dampener positioned to dampenmovement of the microneedle array holder from the retracted position tothe extended position.

The embodiments described above and illustrated in the figures arepresented by way of example only and are not intended as a limitationupon the concepts and principles of the present disclosure. As such, itwill be appreciated by one having ordinary skill in the art that variouschanges in the elements and their configuration and arrangement arepossible without departing from the spirit and scope of the presentdisclosure.

All references and publications cited herein are expressly incorporatedherein by reference in their entirety into this disclosure.

Various features and aspects of the present disclosure are set forth inthe following claims.

What is claimed is:
 1. A microneedle injection and infusion apparatus comprising: a housing having a base and a cavity that extends through the base to define an opening in the base, wherein the base of the housing is configured to be positioned toward a skin surface; a microneedle array holder configured to hold a microneedle array and located in the housing, the microneedle array holder movable with respect to the opening in the base of the housing between a retracted position in which the microneedle array is recessed within the housing such that the microneedle array does not contact the skin surface when the apparatus is positioned on the skin surface and the microneedle array is coupled to the microneedle array holder, and an extended position in which at least a portion of the microneedle array is positioned to contact the skin surface via the opening when the apparatus is positioned on the skin surface and the microneedle array is coupled to the microneedle array holder; a shuttle configured to hold and carry a cartridge, the cartridge defining a reservoir configured to contain an active agent, the shuttle being movable between a first position in which the reservoir of the cartridge is not in fluid communication with a fluid path and a second position in which the reservoir is in fluid communication with the fluid path; and an actuator movable between a first position and a second position, wherein movement of the actuator to the second position releases the shuttle from its first position and allows the shuttle to move toward its second position, and wherein movement of the shuttle toward its second position releases the microneedle array holder from the retracted position and allows the microneedle array holder to move to the extended position; wherein at least a portion of the actuator is located on a lower portion of the housing, wherein the actuator is configured to be moved from the first position to the second position in response to the apparatus being pressed toward a skin surface by pressing on an upper portion of the housing, and wherein the upper portion of the housing is located in an off-axis position with respect to an actuation axis of the actuator.
 2. The apparatus of claim 1, wherein the microneedle array includes a plurality of hollow microneedles, and wherein the fluid path is configured to deliver the active agent to the plurality of hollow microneedles when the microneedle array is coupled to the microneedle array holder.
 3. The apparatus of claim 1, wherein the microneedle array includes a first side comprising a first major surface and a plurality of hollow microneedles that protrude from the first major surface, wherein the microneedle array includes a second side opposite the first side, wherein the plurality of hollow microneedles are in fluid communication with the second side, and wherein the microneedle array is configured to be coupled to a base of the microneedle array holder such that the second side of the microneedle array and the base of the microneedle array holder are spaced a distance apart to define a manifold for the plurality of hollow microneedles.
 4. The apparatus of claim 1, wherein the shuttle is biased in the second position, and wherein the microneedle array holder is biased in the extended position.
 5. The apparatus of claim 1, wherein the microneedle array holder is held in the retracted position by the shuttle, when the shuttle is in its first position.
 6. The apparatus of claim 1, wherein at least a portion of the shuttle is configured to hold the actuator in the second position after the actuator has been moved to the second position.
 7. The apparatus of claim 1, wherein the actuator is held in its second position by the shuttle.
 8. The apparatus of claim 1, wherein the microneedle array holder is movable between the retracted position and the extended position along a first axis, wherein the shuttle is movable between the first position and the second position along a second axis, and wherein the first axis and the second axis are oriented at a non-zero angle with respect to one another.
 9. The apparatus of claim 1, wherein the actuator includes a shuttle stop movable between (i) a first position in which the shuttle stop is positioned to engage at least a portion of the shuttle to hold the shuttle in the first position, and (ii) a second position in which the shuttle stop is no longer positioned to engage the shuttle to hold the shuttle in the first position, such that when the shuttle stop is in the second position, the shuttle is free to move to the second position, and further comprising a stored energy device configured to drive the shuttle toward the second position.
 10. The apparatus of claim 1, wherein the shuttle includes a holder stop movable from (i) a first position in which the holder stop is positioned to engage with at least a portion of the microneedle array holder to hold the microneedle array holder in the retracted position to (ii) a second position in which the holder stop is no longer positioned to engage with the microneedle array holder to hold the microneedle array holder in the retracted position, such that when the holder stop is in the second position, the microneedle array holder is free to move to the extended position, and further comprising a stored energy device configured to drive the microneedle array holder toward the extended position.
 11. The apparatus of claim 1, wherein the actuator is movable with respect to the base of the housing, and wherein when the actuator is in the first position, an outermost surface of the actuator extends beyond the base of the housing by a first distance, and when the actuator is in the second position, the outermost surface of the actuator does not extend beyond the base of the housing, or extends beyond the base of the housing by a second distance that is less than the first distance.
 12. The apparatus of claim 1, wherein the actuator is movable between the first position and the second position along a first actuation axis, wherein the microneedle array holder is movable between the retracted position and the extended position along a second actuation axis, and wherein the first actuation axis and the second actuation axis are substantially parallel with respect to one another.
 13. The apparatus of claim 12, wherein at least a portion of the actuator extends beyond the base of the housing when the actuator is in the first position.
 14. The apparatus of claim 1, wherein the shuttle is movable between the first position and the second position along a third axis, and wherein the third axis is oriented substantially perpendicularly with respect to at least one of the first actuation axis and the second actuation axis.
 15. The apparatus of claim 1, wherein the actuator includes a base and an opening formed in the base, and wherein at least a portion of the microneedle array extends through the opening in the actuator and beyond the base of the actuator when the microneedle array holder is in the extended position, and wherein the base of the actuator is configured to be coupled to the skin surface.
 16. The apparatus of claim 1, wherein, when the actuator is in the first position, at least a portion of the actuator protrudes from the opening in the base of the housing and defines a base of the actuator configured to be coupled to the skin surface, wherein the base of the actuator includes a skin-contact adhesive.
 17. The apparatus of claim 1, wherein the shuttle is biased toward the second position, and wherein the shuttle is restrained from moving to the second position by the actuator, until the actuator is moved to the second position.
 18. The apparatus of claim 1, further comprising a stored energy device configured to drive the shuttle toward the second position.
 19. The apparatus of claim 1, further comprising the active agent and a piston located in the reservoir of the cartridge, the piston movable between a first position in which the active agent is not being forced out of the reservoir and moved into the fluid path and a second position in which the active agent is being forced out of the reservoir and moved into the fluid path.
 20. The apparatus of claim 19, further comprising a first stored energy device configured to initiate movement of the shuttle toward the second position and a second stored energy device configured to assist in moving the shuttle toward the second position and further configured to drive the piston toward its second position.
 21. The apparatus of claim 19, further comprising an indicator that is movable with the piston between the first position and the second position of the piston, wherein the indicator is visible from outside the housing to indicate the position of the piston with respect to the housing.
 22. The apparatus of claim 21, wherein the indicator is movable with the shuttle from the first position of the shuttle to the second position of the shuttle, and wherein the indicator is further movable with the piston and with respect to the shuttle when the shuttle is in the second position.
 23. The apparatus of claim 1, wherein the fluid path includes or is in fluid communication with a piercing element configured to provide fluid communication between the reservoir of the cartridge and the fluid path, and further comprising a deformable sterility seal positioned to enclose the piercing element and configured to be pierced by the piercing element, and wherein the sterility seal is further configured to be changed from a first state in which the sterility seal defines a sterile chamber within which the piercing element is located to a second state in which the sterility seal has been pierced by the piercing element and the sterility seal is collapsed.
 24. A method of using a microneedle injection apparatus, the method comprising: providing a microneedle injection apparatus comprising: a housing having a base and a cavity that extends through the base to define an opening in the base, wherein the base of the housing is configured to be positioned toward a skin surface; a microneedle array holder configured to hold a microneedle array and located in the housing, the microneedle array holder movable with respect to the opening in the base of the housing between a retracted position in which the microneedle array is recessed within the housing such that the microneedle array does not contact the skin surface when the apparatus is positioned on the skin surface and the microneedle array is coupled to the microneedle array holder, and an extended position in which at least a portion of the microneedle array is positioned to contact the skin surface via the opening when the apparatus is positioned on the skin surface and the microneedle array is coupled to the microneedle array holder; a shuttle configured to hold and carry a cartridge, the cartridge defining a reservoir configured to contain an active agent, the shuttle being movable between a first position in which the reservoir is not in fluid communication with a fluid path and a second position in which the reservoir is in fluid communication with the fluid path; and an actuator movable between a first position and a second position; moving the actuator to its second position to allow the shuttle to move toward its second position, wherein movement of the shuttle toward its second position allows the microneedle array holder to move to its extended position; wherein at least a portion of the actuator is located on a lower portion of the housing, wherein the actuator is configured to be moved from the first position to the second position in response to the apparatus being pressed toward a skin surface by pressing on an upper portion of the housing, and wherein the upper portion of the housing is located in an off-axis position with respect to an actuation axis of the actuator. 